In Silico Identification of Spirodioxynaphthalenes as Promising Hsp90 Inhibitors

In Silico Identification of Spirodioxynaphthalenes as Promising Hsp90 Inhibitors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article In Silico Identification of Spirodioxynaphthalenes as Promising Hsp90 Inhibitors Adam Aboalroub This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6199117/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The ATPase activity of Hsp90 is critical for cancer progression, as it maintains the stability of oncogenic proteins, thereby supporting tumor cell survival. Although small-molecule inhibitors targeting this activity have shown preclinical promise, toxicity and insufficient efficacy have hindered their progress in clinical trials. Accordingly, expanding the search for novel Hsp90 inhibitors remains paramount. Spirodioxynaphthalenes, a rapidly expanding class of fungal secondary metabolites, exhibit a remarkable breadth of bioactive properties, including antitumor, antibacterial, antifungal, and enzymatic inhibitory activities. This study employed an in-silico methodology to identify spirodioxynaphthalene derivatives as potential inhibitors of Hsp90’s ATPase activity. We identified thirteen spirodioxynaphthalenes from natural product databases as potential inhibitors of Hsp90 ATPase activity. These compounds, with their favorable drug-like properties, promising predicted pharmacokinetics and cytotoxicity, and potent binding energies ranging from − 10.016 to -10.636 kcal/mol, emerge as compelling candidates for further optimization. Their binding interactions, which reveal key hydrogen bonds and hydrophobic interactions with catalytic residues Lys58, Gly97, and Thr184, bolster their potential as Hsp90 inhibitors. These findings firmly suggest that spirodioxynaphthalenes could represent a novel chemotype for developing Hsp90-targeted cancer therapeutics, providing a ray of hope for the future of cancer treatment. Further mechanistic validation and preclinical development are necessary to advance these compounds towards clinical application. Bioactive small molecules Cancer Hsp90 Molecular docking Spirodioxynaphthalenes Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Natural products represent an affluent source of myriad chemical structures with an expansive spectrum of biological activities, encompassing antimicrobial, anticancer, anti-inflammatory, and enzyme-inhibitory properties [ 1 ]. These naturally occurring compounds, biosynthesized by plants, microorganisms, and marine organisms, frequently exhibit complex and unique molecular architectures that engage biological targets through various mechanisms [ 2 ]. Moreover, numerous compounds were used as efficacious therapeutic agents to treat several pathological conditions, including cancer, infectious diseases, and cardiovascular diseases [ 1 , 2 ]. Remarkably, natural products account for 80% of clinically approved antibiotics and 75% of anticancer drugs [ 3 ]. These agents operate through multifarious mechanisms, as exemplified by paclitaxel ( Taxus brevifolia , Pacific yew tree), which inhibits tubulin polymerization; lovastatin (fungi), which inhibits HMG-CoA reductase; and camptothecin ( Camptotheca acuminata , Chinese happy tree), which inhibits DNA replication [ 4 , 5 ]. Two therapeutic procedures primarily drive the pharmacological treatment of cancer: small molecule-targeted therapy and conventional chemotherapy [ 6 ]. Chemotherapy employs cytotoxic agents to disrupt the cell cycle, targeting the rapid proliferation of cancer cells [ 7 ]. While effective, this approach renders significant side effects (e.g., nausea, vomiting, and mucositis) and the development of multidrug resistance [ 6 ]. In contrast, small molecule targeted therapy (SMTT) focuses on developing chemical entities competent in selectively modulating the activity of biomolecules associated with specific oncogenic processes [ 8 ]. Protein kinases (e.g., BCR-ABL, EGFR, CDK4/6, BRAF), proteases (e.g., the proteasome), and heat shock proteins (e.g., Hsp90) represent prominent targets in SMTT [ 9 ]. Hsp90, a ubiquitous molecular chaperone, is upregulated by cellular stress, protein misfolding, oxidative stress, and the tumor microenvironment [ 10 ]. In these circumstances, Hsp90 employs the energy of ATP hydrolysis to assist in the folding and maintaining the stability of hundreds of client proteins [ 11 ]. Hsp90 clients, including kinases, ligases, and transcription factors, are entangled in essential cellular processes such as signal transduction, cell cycle regulation, and apoptosis [ 12 ]. Hsp90 is a dimeric protein, with each proteome comprising three structural domains. The N-terminal domain (NTD) of Hsp90 contains the ATP-binding pocket, the middle domain (MD) interacts with client proteins, and the C-terminal domain (CTD) promotes dimerization [ 13 ]. The high dynamicity of Hsp90 protomers allows them to experience conformational changes triggered by ATP binding and hydrolysis, which is indispensable for Hsp90 chaperone roles [ 14 ]. Hsp90 cochaperones stabilize Hsp90 conformations throughout the ATPase cycle and recruit client proteins to the Hsp90 chaperone machinery [ 12 ]. The Hsp90 chaperone cycle exhibits high selectivity, specifically targeting proteins with an intrinsic unfolding or low folding propensity to facilitate proper folding and stability [ 10 , 14 ]. A considerable number of the Hsp90 client proteins are related to the pathogenesis of numerous diseases, including nondegenerative diseases like Alzheimer's disease, Parkinson's disease, and many types of cancer [ 15 , 16 ]. Preclinical studies have indicated that breast cancer and melanoma cells depend highly on Hsp90 for stabilizing proteins such as HER2 and BRAF [ 17 ]. This enhanced dependency renders these neoplastic cells notably exposed to the action of Hsp90 inhibitors, which exert their therapeutic consequence by attaching to Hsp90 and disrupting the folding of these vital proteins, thereby establishing Hsp90 inhibition as a promising therapeutic strategy for treating myriad malignancies [ 18 ]. According to the DrugBank database, 49 Hsp90-based inhibitors have been assessed in clinical trials for cancer treatment; however, prior to contemporary developments, none had acquired regulatory approval due to impediments in efficacy or dose-dependent toxicity profiles [ 19 ]. The recent regulatory approval of Pimitespib (TAS-116), the first therapeutic agent specifically targeting Hsp90-driven tumorigenesis, constitutes a substantial milestone [ 20 ]. Pimitespib's mechanism of action involves binding to and inhibiting both Hsp90 α and β isoforms, culminating in the degradation of oncogenic client proteins, the induction of apoptosis, and the suppression of neoplastic cell proliferation [ 19 , 20 ]. Hsp90 inhibitors may be categorized based on their mechanism of action, with classes including N-terminal, C-terminal, or middle-domain inhibitors [ 21 ]. Geldanamycin (GDA), recognized as the first N-terminal Hsp90 inhibitor, was isolated from the actinomycete Streptomyces hygroscopicus variety geldanus [ 22 ]. GDA executes its antitumor action by association with Hsp90, precluding the activation of oncogenic client proteins and thereby leading to cancer cell degradation [ 19 , 22 ]. Numerous GDA derivatives with enriched solubility, reduced toxicity, and enhanced anticancer properties were developed, including 17-AAG and 17-DMAG [ 19 , 23 ]. Likewise, the fungal natural product radicicol potently targets Hsp90's NTD, disrupting its interaction with oncogenic proteins such as Raf and Src, thus normalizing cancer cells. Despite powerful in vitro antitumor activity, its poor in vivo stability curbed its clinical potential [ 19 , 24 ]. Consequently, more stable and active analogs, including NVP-AUY922 (Luminespib), AT-13387 (onalespib), and STA-9090 (ganetespib), have been developed [ 25 , 26 ]. The capability of Hsp90's NTD inhibitors to orchestrate the functional consequences of the Hsp90 chaperone cycle and elicit diverse therapeutic effects makes them promising candidates for developing therapeutic interventions against both neoplastic and neurological disorders. Spirodioxynaphthalenes, an expanding class of fungal secondary metabolites, are distinguished by two 1,8-dihydroxynaphthalene-derived spiroketal units merged by a spiroketal linkage [ 27 ]. Based on their structural characteristics, spirodioxynaphthalenes are categorized into several subclasses, including preussomerins, palmarumycins, rhytidones, rhytidenones, anteaglonialides, cladospirones, guignardins, diepoxines, ascochytatins, and decaspirones [ 27 , 28 ]. Spirodioxynaphthalenes are biosynthesized via polyketide pathways involving oxidative coupling or enzymatic transformations to form the spiro linkage [ 29 ]. The chemical structure of spirodioxynaphthalenes is characterized by two distinct features: a core structure in which a quaternary carbon atom (the spiro center) connects two naphthalene rings and the presence of various hydroxy, methoxy, and carbonyl functional groups [ 27 – 29 ]. The distinct structural features of these spirodioxynaphthalenes are crucial to their varied biological impacts, which span antitumor and antimicrobial activities, as well as enzymatic inhibition [ 30 ]. This selective cytotoxicity, observed in multiple studies, makes them promising candidates for drug development [ 27 , 28 ]. Traditionally, bioactive compounds are discovered via hands-on methods like bioactivity-guided isolation [ 3 ]. This practice involves screening a crude extract from a natural resource to specify potential bioactive compounds. Then, the crude is fractionated into small parts and analyzed to affirm the bioactivity of any determined hit [ 2 ]. The extensive efforts of scientists in determining and characterizing natural products have resulted in hundreds of thousands of unique entries in databases such as COCONUT, NP Atlas, and Natural Products Online (which hosts the LOTUS depository) [ 31 – 33 ]. Among these are hundreds of spirodioxynaphthalenes with uncharacterized biological impacts. While exploring the biological activities of natural products using classical detection methods is often constrained by financial and resource limitations, the emergence of computer-aided approaches like virtual screening and molecular docking has revolutionized drug discovery [ 34 ]. These methods deliver a robust and reliable alternative, promising a bright future for recognizing targets and characterizing the potential activities of natural products. This study used in silico methods to virtually screen natural product databases and identify potential inhibitors targeting the ATP binding pocket within Hsp90. Thirteen spirodioxynaphthalenes were identified from natural product databases as potential Hsp90 ATPase inhibitors. These compounds exhibit favorable drug-like properties, promising pharmacokinetic profiles, and cytotoxic potential. Their strong binding affinities, ranging from − 10.016 to -10.636 kcal/mol, highlight their suitability for further optimization. Analysis of their binding interactions reveals critical hydrogen bond and hydrophobic interactions with key catalytic residues, including Lys58, Gly97, and Thr184, reinforcing their potential as Hsp90 inhibitors. These findings suggest that spirodioxynaphthalenes represent a novel chemotype for developing Hsp90-targeted cancer therapeutics. Further mechanistic validation and preclinical studies are required to advance these compounds toward clinical application. 2. Materials and Methods 2.1 Spirodioxynaphthalenes structure preparation MK 3018, the first identified spirodioxynaphthalene, served as a model compound for in-silico screening of natural product databases, including COCONUT, NP Atlas, LOTUS, and PubChem, to identify related derivatives. These databases are valuable resources for computational studies such as molecular docking and virtual screening because they provide information about the spatial arrangement of atoms in these molecules. From these databases, 222 spirodioxynaphthalene structures were selected using a Tanimoto similarity threshold of 80% compared to the model compound (see Table S1) [ 35 ]. The SMILES representations for the selected compounds were obtained and prepared for computational analysis. 2.2 Screening of the Hsp90 inhibitor-like compounds using docking-based virtual screening To screen our spirodioxynaphthalene library for potential activity against Hsp90, the X-ray crystal structure of the Hsp90-NTD (PDB ID: 6LTI, resolution: 1.59 Å) was downloaded and prepared for molecular docking studies using AutoDock Vina 1.2.0 [ 36 ]. AutoDock Vina is a widely used molecular docking software tool that provides accurate, fast, and easy-to-use prediction of small molecules' binding mode and affinity to their biological targets [ 37 ]. The grid defining the receptor's active site was generated using two cuboidal boxes: a larger box with dimensions 33 x 14 x 20 Å and a smaller box with dimensions 20 x 20 x 20 Å to facilitate accurate binding calculations. Docking simulations were performed using standard settings and a Lamarckian genetic algorithm, running 100 times for each ligand [ 38 ]. The results were analyzed from the AutoDock log files, focusing on the lowest energy of binding (LEB) to identify the most energetically favorable binding pose (conformer). The selected conformers were exported and visualized using the UCSF Chimera package to analyze the binding modes of the identified compounds with the Hsp90 protein [ 39 ]. Based on their docking score, 13 of the docked complexes were selected for further analysis. These complexes were ranked by binding score and interaction pose, with those exhibiting negative binding energies considered to have higher potential stability. The docking results were validated using SwissDock Attracting Cavities (AC) 2.0 [ 40 ]. SwissDock's AC 2.0 is an advanced molecular docking algorithm that predicts small molecule binding to protein targets with greater flexibility, robustness, speed, and accuracy. The human Hsp90 protein structure (PDB ID: 6LTI) was similarly prepared before docking. A 20x20x20 Å docking grid centered at 32-13-20 Å was defined, and docking was performed using four Rapid Initial Conformations (RICs), high sampling exhaustivity, and a focus on buried cavities. The resulting docking data were then downloaded and visualized using UCSF Chimera. 2.3 Validation of the Binding Mode Between Spirodioxynaphthalenes and Hsp90 To gain deeper insights into the interaction between top-ranked spirodioxynaphthalene derivatives and the Hsp90 N-terminal domain (NTD), molecular docking analysis was repeated using a mutated protein. This approach allowed for identifying potential binding hot spots and evaluating the effects of specific amino acid substitutions on ligand affinity. We used PyMOL 2.1 to introduce a point mutation in residues critical for spirodioxynaphthalenes interaction [ 41 ]. The mutation was performed utilizing PyMOL’s Mutagenesis Wizard, which enables precise residue modifications and structural preparation for subsequent computational analysis and molecular dynamics simulations. The modified protein structure (PDB ID: 6LTI) was then subjected to docking studies with the top-ranked molecules from the initial screening. The docking results were analyzed and visualized using UCSF Chimera, allowing for a detailed assessment of changes in binding affinity and interaction patterns resulting from the mutation. This analysis provided valuable insights into the functional significance of the key residues like Lys58 and Thr184 in ligand binding and contributed to a more comprehensive understanding of the molecular mechanisms underlying Hsp90 inhibition. 2.4 In-silico cytotoxicity prediction in tumor cell lines Cell-line cytotoxicity assays are routinely utilized in drug discovery to study potential anticancer agents and assess their safety. In this regard, computational-based examination of cytotoxicity against hundreds of tumor cell lines extensively reduces the time and expense of drug development and candidate evaluation [ 42 ]. CLC-Pred 2.0 (Cell Line Cytotoxicity Predictor) is a web-based platform designed for the in-silico prediction of compound cytotoxicity in non-transformed and transformed (cancer) cell lines, utilizing structural formulas as input [ 43 ]. CLC-Pred employs Quantitative Structure-Activity Relationship (QSAR) models, trained using experimental cytotoxicity data from numerous cell lines, to predict activity by comparing the structural features of the input compound with those present in its database. The potential cytotoxicity of the top-ranked selected molecules against cell lines was predicted using the CLC-Pred 2.0 platform ( https://www.way2drug.com/Cell-line ) by inputting their SMILES representations. 2.5 Spirodioxynaphthalenes physicochemical, pharmacokinetics, drug-likeness, and medicinal chemistry properties assessment The thirteen top-ranked compounds were subjected to Absorption, Distribution, Metabolism, and Excretion (ADME) analysis and evaluation of their drug-likeness and medicinal chemistry properties using the Expasy SwissADME online service [ 44 , 45 ]. This analysis examines several crucial physicochemical properties of the molecule. These include molecular weight; topological polar surface area (TPSA), which indicates the molecule's ability to interact with water and biological membranes; the number of rotatable bonds; the number of hydrogen bond donors and acceptors; lipophilicity (LogP), a measure of its hydrophobicity and influence on membrane permeability; and solubility (LogS). The drug-likeness properties of the molecules were evaluated using Lipinski's Rule of Five as a predictor of oral bioavailability [ 46 ]. Subsequent filtering using the Ghose, Veber, Egan, and Muegge criteria further refined the assessment of their suitability as drug candidates. Finally, these molecules were assessed for medicinal chemistry properties, including lead likeness (suitability for optimization) and synthetic accessibility (SA score, reflecting the ease of chemical synthesis) to determine the potential optimization of these molecules into drugs. 3. Results and discussion Natural products represent a significant reservoir of bioactive compounds characterized by novel chemical scaffolds [ 2 , 3 ]. In-silico methodologies are increasingly recognized as robust and reliable complements to traditional in vitro techniques in discovering bioactive molecules [ 34 ]. The extensive repositories of compounds with uncharacterized biological activities available in current databases provide a unique opportunity for computer-aided investigations to rapidly screen for potentially active molecules, identify their biological targets, and elucidate their mechanisms of action. Computational methods were employed in this study to identify spirodioxynaphthalene derivatives as potential modulators of Hsp90 oncogenic activity. As a growing class of fungal secondary metabolites with distinctive architectures and diverse bioactivities, including antitumor and antibacterial properties, spirodioxynaphthalenes represent valuable lead compounds for medicinal chemistry. 3.1 Natural Databases screening Natural compound databases and their derivatives were screened using an 80% Tanimoto similarity threshold and Lipinski’s Rule of Five, resulting in a library of 222 compounds. This library, presented in Table S1, includes the corresponding SMILES structures and natural product database identifiers and is the foundation for further investigations in this study. 3.2 Dockingbased virtual screening analysis Docking-based virtual screening of the 222 screened compounds (AutoDock Vina 1.2.0) revealed a range of predicted binding energies. Notably, 13 compounds displayed the most substantial binding, with LBEs ranging from − 10.016 to -10.636 kcal/mol (Fig. 1 and Table 1 ). The remaining compounds were distributed as follows: 108 compounds from − 9.004 to -9.972 kcal/mol, 75 compounds from − 8.000 to -8.995 kcal/mol, and 24 compounds from − 2.703 to -7.961 kcal/mol (Table S1). Sparticolin G, with an LBE of -10.636 kcal/mol, stands out among these 13 spirodioxynaphthalenes. This compound belongs to the sparticolin family (A-G), a group of biologically active oxidized spirodioxynaphthalenes isolated from the Ascomycete fungus Sparticola junci [ 47 ]. Sparticolin G has shown promising antifungal activity against various fungal species, including Schizosaccharomyces pombe and Mucor hiemalis . While exhibiting cytotoxicity against seven mammalian cell lines, it warrants further investigation as a potential lead compound for developing novel inhibitors. Table 1 Predicted binding affinities (LBE values) and SMILES representations of spirodioxynaphthalene derivatives with high affinity for Hsp90 Compound SMILES LBE (kcal/mol) Sparticolin G C1C = CC(= O)[C@@]12C3(C = CC(= O)O2)OC4 = CC = CC5 = C4C(= CC = C5)O3 -10.636 Preussomerin B C1C[C@]23C4 = C([C@H]1O)C = CC = C4O[C@@]5(O2)[C@H]6[C@H](O6)[C@@H](C7 = C(C = CC(= C57)O3)O)O -10.417 Diepoxine Alpha C1CC(= O)[C@@]23[C@@]([C@H]1O)(O2)C(= O)[C@@H]4[C@H](C35OC6 = CC = CC7 = C6C(= CC = C7)O5)O4 -10.348 Guignardin B C1 = CC2 = C3C(= C1)OC4([C@@H]([C@H]5[C@H](O5)C6 = C4C = CC = C6O)O)OC3 = CC = C2 -10.263 Diepoxine Sigma C1 = CC2 = C3C(= C1)OC4([C@@H]5[C@@H](O5)C(= O)[C@]67[C@]4(O6)C(= O)C = C[C@H]7O)OC3 = CC = C2 -10.200 Anteaglonialide F C1CC(= O)O[C@H]1[C@@H]2CC(= O)C = CC23OC4 = CC = CC5 = C4C(= CC = C5)O3 -10.179 Preussomerin D C1 = CC2 = C3C(= C1)O[C@@]45[C@H]6[C@H](O6)[C@@H](C7 = C(C = CC(= C74)O[C@@]3(O5)C = CC2 = O)O)O -10.165 Anteaglonialide E C1CC(= O)O[C@H]1[C@@H]2CC(= O)CCC23OC4 = CC = CC5 = C4C(= CC = C5)O3 -10.141 Palmarumycin M2 C1C[C@H]([C@@H]2[C@@H]([C@H]1O)C(= O)C[C@H](C23OC4 = CC = CC5 = C4C(= CC = C5)O3)O)O -10.134 Sch53514 C1 = CC2 = C3C(= C1)OC4([C@H]5[C@H](O5)[C@@H]([C@@]67[C@@]4(O6)C(= O)C = C[C@@H]7O)O)OC3 = CC = C2 -10.109 Preussomerin E C1 = CC2 = C3C(= C1)O[C@@]45[C@H]6[C@H](O6)C(= O)C7 = C(C = CC(= C74)O[C@@]3(O5)C = C[C@@H]2O)O -10.088 Palmarumycin CE2 C1C[C@H]([C@@H]2[C@H]([C@H]1O)C(= O)CCC23OC4 = CC = CC5 = C4C(= CC = C5)O3)O -10.021 Decaspirone F C1 = CC2 = C3C(= C1)OC4(C = C[C@@H]([C@H]5[C@H]4[C@@H](C = C[C@@H]5O)O)O)OC3 = CC = C2 -10.016 3.3 Detailed analysis of spirodioxynaphthalene substructures for potential Hsp90 inhibition Spirodioxynaphthalenes, diverse spirocyclic fungal metabolites, exhibit significant antitumor, antimicrobial, and enzymatic inhibition activities [ 30 ]. Biosynthesized through modified polyketide pathways, they encompass various structural subclasses, including preussomerins and guignardins [ 27 ].We performed molecular docking analysis to evaluate their potential as Hsp90 ATPase inhibitors, comparing their binding modes and affinities with ATP. Results demonstrated that spirodioxynaphthalenes bind to the same region of the Hsp90 NTD as ATP, exhibiting similar binding modes within the ATP-binding site (Fig. 2 , Table 3 , and Fig. 3 ). These findings suggest spirodioxynaphthalenes compete with ATP for binding, likely acting as ATP-competitive inhibitors of Hsp90's chaperone activity. ATP interacts with Hsp90 via a combination of hydrogen bonds (Lys58, Glu47, Leu107, Phe138, Gly97, Thr152, Thr184) and hydrophobic interactions (Lys58, Leu107, Ile96, Gly97, Met98, Ala55, Asn51) (Table 3 and Fig. 2 ). Notably, spirodioxynaphthalenes adopt a similar binding mode within the Hsp90 NTD (Table 3 , Fig. 3 ), directly competing with ATP for occupancy of the catalytic pocket. This structural mimicry strongly supports their potential as ATP-competitive inhibitors, effectively targeting Hsp90 ATPase activity for therapeutic intervention. Molecular docking analysis of spirodioxynaphthalene substructures revealed a range of ligand binding energy values (Table 2 ), indicating their differing binding affinities. Table 2 Calculated LBE values for spirodioxynaphthalene substructures docked to the N-terminal domain of Hsp90. Subfamily Compound LBE (kcal/mol) Compound LBE (kcal/mol) Compound LBE (kcal/mol) Sparticolin A -9.336 D -9.059 G -10.636 B -9.429 E -8.763 C -7.971 F -9.334 Preussomerin A -9.939 I -8.427 Ymf 1029A -8.956 B -10.417 J -7.729 Ymf 1029B -9.113 C -8.502 K -8.711 Ymf 1029C -8.868 D -10.165 L -8.458 Ymf 1029D -9.806 E -10.088 EG1 -9.459 Ymf 1029E -8.277 F -9.806 EG2 -8.895 Chloropreussomerin A -6.133 G -9.874 EG3 -9.585 Chloropreussomerin B -5.387 H -9.368 EG4 -8.713 3'-O-Desmethyl-1-epipreussomerin C -8.932 Palmarumycin M1 -9.38 B7 -8.074 C15 -9.565 M2 -10.134 B8 -8.141 C16 -9.489 CE1 -9.703 B9 -7.841 CP1 -9.433 CE2 -10.021 C1 -9.535 CP2 -9.204 CE3 -8.043 C2 -9.731 CP3 -9.511 CE4 -9.056 C3 -8.531 CP3a -9.354 P1 -9.615 C4 -9.071 CP4a -8.786 P2 -9.047 C5 -8.844 CP4 -9.16 P3 -8.972 C6 -8.853 CP5 -9.577 P4 -8.323 C7 -8.907 CP17 -8.824 P5 -9.379 C8 -9.438 CP18 -9.333 B1 -8.631 C9 -9.066 LP1 -8.477 B2 -8.713 C10 -8.657 CR1 -9.558 B3 -8.719 C11 -9.608 Palmarumycin derivative 3 -8.242 B4 -8.43 C12 -8.569 Palmarmycin BG-1 -8.951 B5 -9.279 C13 -9.851 Palmarmycin JC 1 -9.422 B6 -9.911 C14 NA Rhytidone A -9.023 B -8.992 C -8.986 Rhytidenone A -2.696 D -9.424 G -9.320 B -9.283 E -9.456 H -6.784 C -9.410 F -9.688 Anteaglonialide A -9.327 C -8.776 E -10.141 B -9.807 D -9.102 F -10.179 Cladospirone bisepoxide -9.556 D -9.397 G -8.175 B -8.941 E -9.038 H -8.674 C -8.736 F -8.183 I -8.826 Guignardin A -8.284 C -9.613 E -9.087 B -10.263 D -7.033 F -9.657 Diepoxine Alpha -10.348 Kappa -7.512 Delta -8.164 Sigma -10.200 G -8.831 Ascochytatin -7.948 Decaspirone A -9.337 D -7.008 G -9.711 B -7.561 E -7.565 H -9.275 C -9.497 F -10.016 I -9.197 Unclassified Spirodioxynaphthalenes SCH-53823 -9.658 CID: 162959954 -9.140 CID: 156020160 -9.748 Sch53514 -10.109 CID: 162988669 -9.427 CID: 162848350 -8.768 CJ-12,371 -9.416 CID: 163065359 -9.745 CID: 162914941 -8.020 CID: 10044524 -9.524 CID: 155518452 -8.755 CID: 162926480 -9.593 CID: 162951024 -8.490 CID: 155532397 -9.003 CID: 134145504 -9.572 CID: 162957149 -9.588 CID: 155555809 -8.867 CID: 134153360 -9.436 CID: 102223268 -9.265 CID: 102069972 -8.795 CID: 51354124 -9.443 CID: 102223269 -9.327 CID: 101671799 -9.434 CID: 3010883 -9.352 CID: 15224599 -8.057 CID: 101672291 -9.425 3.3.1 Sparticolin subfamily To investigate whether other members of the sparticolin family also exhibit Hsp90 affinity, we performed molecular docking simulations to assess the potential binding interactions between Hsp90 and each family member (A, B, C, D, E, and F) [ 47 ]. In the analysis of the resulting docking scores, we found that sparticolin A has LBE value of -9.336 kcal/mol, sparticolin B has LBE value of -9.429 kcal/mol, sparticolin C has LBE value of -7.971 kcal/mol, sparticolin D has LBE value of -9.059 kcal/mol, sparticolin E has LBE value of -8.763 kcal/mol, Table. 2. Sparticolin F has LBE value of -9.334 kcal/mol. The observed difference in binding affinity, with sparticolin G exhibiting a 1.207 kcal/mol higher than the next closest family member (sparticolin B), is attributed to its distinct structural features. The X-ray crystallographic guided structure analysis revealed that these molecules share a common spirodioxynaphthalene core, in addition to carboxyalkylidene-cyclopentanoid (sparticolin A–D), carboxyl-functionalized oxabicyclo[3.3.0]octane (sparticolin E–F), and annelated 2-cyclopentenone/δ-lactone (sparticolin G) [ 47 ]. The presence of a fused 2-cyclopentenone/δ-lactone motif can significantly impact a molecule's bioactivity by modulating its structural, electronic, and reactive characteristics. Docking analysis indicated that the cyclopentenone moiety of sparticolin G engages in multiple interactions with the Hsp90, including an ion-π interaction with Lys58, hydrophobic contacts with Lys58, Ala55, Asn51, Leu107, and Thr184, and a hydrogen bond with Lys58, Gly97, Thr109, Ile110, and Thr184, Table. 3, Figure. 3, and Figure. 4. The δ-lactone moiety also contributes to binding, forming a hydrogen bond with Lys58 and hydrophobic interactions with Asn51. These findings collectively further support that the fused 2-cyclopentenone/δ-lactone system significantly enhances the binding affinity of sparticolin G. Table 3 Molecular docking analysis of the top-ranked spirodioxynaphthalene derivatives binding to the Hsp90’s NTD: interaction profiles and the lowest binding energies Compound Interaction Mode LBE (kcal/mol) H-bond Hydrophobic ion-π Sparticolin G Lys58, Gly97, Thr109, Ile110, Thr184 Lys58, Ala55, Asn51, Leu107, Thr184 Lys58 -10.636 Preussomerin B Lys58, Gly97, Thr109, Thr184 Lys58, Val186, Ala55, Thr184, Asn51, Leu107 - -10.417 Preussomerin D Lys58, Gly108, Thr109, Leu107, Thr184, and Gly97 Val186, Thr184, Phe138, Asn51, Leu107 - -10.165 Preussomerin E Lys58, Gly97, Asn51, Ile91, Thr184, and Thr152 Ile96, Ala55, Leu107, Phe138, Val186, Asn51 - -10.088 Palmarumycin M2 Lys58, Gly97, Thr109, Asp102, and Thr152 Ile96, Phe138, Asn51, Leu107, Thr184, and Val186 - -10.134 Palmarumycin CE2 Lys58, Asn51, Ser52, Thr109, Gly97, Thr152, Asn51, Ile96, Phe138, Leu107, Val186, Thr184 - -10.021 Anteaglonialide E Lys58, Gly97, Thr184, Thr109, Phe138, Thr184, Val186, Ile96, Asn51, and Ala55 Lys58 -10.141 Anteaglonialide F Lys58, Gly97, Thr184, Thr109, Lys58, Gly108, Asn51, Thr184, and Leu107 Lys58 -10.179 Guignardin B Lys58, Leu48, Asn51, Gly97, Thr184, Thr109 Lys58, Asn51, Ala55, Val186, Leu107 - -10.263 Diepoxine Alpha Lys58, Gly97, Leu107, Ile96, Thr109, Thr184, and Thr152 Ala55, Lys58, Val186, Asn51, Gly108, Leu107 - -10.348 Diepoxine Sigma Lys58, Ile96, Thr109, Gly97, Leu107, Thr152, and Thr184 Ala55, Lys58, Gly108, Leu107, Val186, Asn51, Thr184 - -10.200 Decaspirone F Lys58, Asn51, Glu74, Gly135, Thr184, and Thr152 Lys58, Leu107, Phe138, Asn51, Thr184, Gly108, and Val186 - -10.016 Sch53514 Lys58, Gly97, Thr184, Thr109, and Thr152 Lys58, Val186, Leu107, Ala55, Gly108, Asn51, Thr184, Lys58 - -10.109 Palmarumycin B6 Lys58, Gly97, Thr184, Thr109 Lys58, Thr184, Asn51, Leu107, Val186 - -9.911 Palmarumycin C13 Lys58, Gly97, Thr184, Thr109 Lys58, Asn51, Leu107, Val186 - -9.851 Decaspirone G Lys58, Gly97, Thr184, Thr109 Lys58, Asn51, Leu107, Phe138, Met98 - -9.711 Rhytidenone F Lys58, Gly97, Thr184, and Thr109 Lys58, Asn51, Phe138 -9.688 Guignardin F Lys58, Gly97, Thr184 Lys58, Asn51, and Leu107, Phe138, Thr184, Asp93 - -9.657 Cladospirone bisepoxide Lys58, Gly97, Thr152, Thr184, Gly135 Asn51, Lys58, Leu107, Val186 -9.556 Ascochytatin Lys58, Gly97, Thr109, Thr152, Thr184, Phe138 Asn51, Gly97, Thr184, Leu107, Thr109, Val136, Phe138 -7.948 ATP Lys58, Glu47, Leu107, Phe138, Gly97, Thr152, Thr184 Lys58, Leu107, Ile96, Gly 97, Met98, Ala55, Asn51, Thr184 -7.866 3.3.2 Preussomerins subfamily Preussomerins are spirodioxynaphthalene derivatives characterized by a core structure of two unsaturated decalin units linked by three oxygen bridges via two spiroketal carbons, one on each decalin unit [ 48 , 49 ]. The preussomerin family was first recognized in 1990 with the characterization of preussomerin A from the coprophilous fungus Preussia isomera [ 49 ]. Subsequently, approximately 20 analogs, encompassing preussomerins A–L, Ymf 1029 A–E, and preussomerins EG1–EG4, have been isolated from diverse fungal sources, including Preussia isomera , Sporormiella vexans , and Edenia gomezpompae [ 50 ]. These metabolites demonstrated various bioactivities, including antimicrobial, nematicidal, and cytotoxic, and numerous members of this family have been reported to have antitumor activity [ 48 – 50 ]. Chen et al. have reported that several members of this family demonstrated potent antiproliferative activity against A549, HepG2, and MCF-7 human cancer cell lines, with IC50 values ranging from 2.5–9.4 micromolar [ 51 ]. Molecular docking analysis revealed distinct binding modes and affinities of preussomerins to Hsp90 (Table. 2). Preussomerin B exhibited a high binding affinity with a calculated ligand binding energy of -10.417 kcal/mol. At the same time, preussomerin J demonstrated a weaker interaction with Hsp90, exhibiting an LBE of -7.729 kcal/mol (Table. 2). Preussomerin B, a metabolite produced by the coprophilous fungus Preussia isomera Cain, possesses a broad spectrum of biological influences [ 49 ]. Molecular docking analysis revealed that this bioactive compound interacts favorably with the Hsp90 ATPase domain, exhibiting a calculated binding energy of -10.417 kcal/mol. This strong binding suggests the compound's potential as a potent inhibitor of Hsp90 ATPase activity. Preussomerin B binds to Hsp90 through a combination of hydrophobic and hydrogen-bonding interactions. Its rigid bicyclic diterpene core contributes to hydrophobic interactions with Lys58, Val186, Ala55, Thr184, Asn51, and Leu107 of Hsp90. Furthermore, the hydroxy groups on the fused rings are crucial for solubility and form hydrogen bonds with Lys58, Gly97, Thr109, and Thr184 (Table 3 and Fig. 3 ). Preussomerin D, a secondary metabolite from Preussia cinerascens , shows promise as a nematicide against Bursaphelenchus xylophilus , as an inhibitor of coelomycetous fungi in dung, and as a potent inhibitor of Ras farnesyl-protein transferase (FPTase), suggesting potential therapeutic applications [ 52 ]. Molecular docking analysis revealed that this bioactive compound interacts favorably with the Hsp90 ATPase domain, exhibiting a calculated binding energy of -10.165 kcal/mol (Table 3 ). This strong binding suggests the compound's potential as a potent inhibitor of Hsp90 ATPase activity. The core of Preussomerin D is a spiro[4.5]decane system, which is constructed by the fusion of two rings: a cyclohexane ring and a cyclopentane ring. The cyclohexane ring is fused to a pyran ring, while the cyclopentane ring is fused to a lactone ring. This fused ring system contributes to hydrophobic interactions with Val186, Thr184, Phe138, Asn51, and Leu107 of Hsp90. Preussomerin D's spirocyclic core features diverse oxygen-containing functional groups—including hydroxy, a ketone, and an ether, which contribute to its biological activity, molecule solubility, and its H-bonds interaction with Lys58, Gly108, Thr109, Leu107, Thr184, and Gly97 of Hsp90, Table.3 and Figure. S1. Preussomerin E, a secondary metabolite isolated from the fungus Preussia isomera , displays a broad spectrum of biological activities. Notably, it exhibits antifungal properties and demonstrates significant cytotoxicity against various cancer cell lines, suggesting promising antitumor potential [ 53 ]. Molecular docking studies revealed a favorable interaction between Preussomerin E and the ATPase domain of Hsp90, with a calculated binding energy of -10.088 kcal/mol, Table 2 . This strong binding affinity suggests that Preussomerin E may act as a potent inhibitor of Hsp90 ATPase activity. Preussomerin E possesses a unique pentacyclic ring system formed by the fusion of a 1,4-dihydronaphthalene (a benzene ring fused to a cyclohexene) and a 1-tetralone (a benzene ring fused to a cyclohexanone), linked by three oxygen bridges. This architecture facilitates hydrophobic interactions with key residues of Hsp90, including Ile96, Ala55, Leu107, Phe138, Val186, and Asn51. Additionally, two hydroxy substituents contribute to hydrogen bonding with Lys58, Gly97, Asn51, Ile91, Thr184, and Thr152 of Hsp90 (Table 3 and Figure S1). A unique subgroup of preussomerins exists, characterized by incorporating chlorine atoms within their structure. Chloropreussomerins A and B, isolated from Lasiodiplodia theobromae ZJ-HQ1, exemplify this subgroup as the first reported chlorinated preussomerins [ 53 ]. These compounds possess a distinctive chlorine atom at the C-8 position of their naphthalene core. Molecular docking analysis revealed that the chloride substituent in chloropreussomerins did not enhance but instead impaired binding affinity to Hsp90’s ATP-binding pocket. Specifically, Chloropreussomerin A and Chloropreussomerin B exhibited ligand binding energies (LBE) of -6.133 kcal/mol and − 5.387 kcal/mol, respectively—values significantly weaker than those of non-chlorinated preussomerin derivatives (e.g., preussomerins B: -10.417 kcal/mol), Table.2. This suggests that the electron-withdrawing chloride group disrupts critical interactions, reducing Hsp90 inhibitory efficacy. 3.3.3 Anteaglonialides subfamily The anteaglonialides family, a diverse group of spirodioxynaphthalene natural products, originates from the endophytic fungus Anteaglonium sp. FL0768 [ 54 ]. This fungus resides within the tissues of the spikemoss Selaginella arenicola. The Anteaglonialide family, incorporating members such as Anteaglonialides A-F, has exhibited various biological activities, including antibacterial, antifungal, and cytotoxic influences [ 54 ]. The chemical structure of the anteaglonialides features a shared core motif, 1,8-spirodioxynaphthalene, which is linked to cyclohexane derivatives. These cyclohexane units are further connected to a γ-lactone moiety, completing the complex architecture of the molecule. This unique arrangement of rings and functional groups contributes to the structural diversity and biological activity of the anteaglonialides. Molecular docking analysis revealed that the tested compounds exhibit moderate to strong binding affinity to Hsp90 (Table. 2). Binding affinity was quantified using calculated LBE values. The following LBE values (kcal/mol) were obtained: Anteaglonialide A (-9.327), Anteaglonialide B (-9.807), Anteaglonialide C (-8.776), Anteaglonialide D (-9.102), Anteaglonialide E (-10.141), and Anteaglonialide F (-10.179). Anteaglonialide F and Anteaglonialide E demonstrated the highest binding affinity among the tested compounds, suggesting their potential as a potent Hsp90 inhibitor. Anteaglonialide E binds to Hsp90 through a combination of interactions. A hydrogen bond is formed between the ketone oxygen of its cyclohexanone ring and Lys58, Gly97, Thr184, and Thr109 of Hsp90. Additionally, the lactone ring of Anteaglonialide E participates in an ion-π interaction with Lys58, Figure. 4. Several residues, including Phe138, Thr184, Val186, Ile96, Asn51, and Ala55, contribute to hydrophobic interactions with different parts of Anteaglonialide E, Figure. 3 and Table. 3. Anteaglonialide F binds to Hsp90 through a combination of diverse interactions. A hydrogen bond is established between the ketone oxygen of its cyclohexenone ring and Lys58, Gly97, Thr184, and Thr109 of Hsp90. Furthermore, the lactone ring of Anteaglonialide F engages in an ion-π interaction with Lys58, Figure. 4. Additionally, multiple residues—including Lys58, Gly108, Asn51, Thr184, and Leu107—contribute to hydrophobic interactions with various regions of Anteaglonialide F, enhancing its binding stability and affinity (Table 3 and Fig. 3 ). 3.3.4 Palmarumycins subfamily Palmarumycins are about 50 members of natural products classified as spirodioxynaphthalenes [ 28 ]. These secondary metabolites are synthesized by various fungi, particularly species belonging to the Diaporthe and Coniothyrium genera [ 55 ]. Their distinctive structural features have attracted considerable interest owing to their unique chemical frameworks and broad spectrum of biological activities, such as antimicrobial, antifungal, antitumor, and antiviral properties [ 55 ]. These structurally distinct antibiotics possess a unique architecture characterized by a 1,8-dihydroxy naphthalene unit spiro cyclically linked to a partially reduced naphthalene ring. This core scaffold is further adorned with various substituents, including hydroxy and chloride groups, significantly contributing to their structural diversity and biological activity. Molecular docking analysis revealed that the tested Palmarumycin compounds displayed moderate to strong binding affinities to Hsp90, ranging from − 7.841 kcal/mol for Palmarumycin B9 to -10.134 kcal/mol for Palmarumycin M2 and − 10.021 kcal/mol for Palmarumycin CE2 (Table 2 ). Palmarumycin M2, a spirodioxynaphthalene compound, originates from Microsphaeropsis arundinis , a coelomycetous fungus that inhabits plants [ 55 , 56 ]. Palmarumycin M2 interacts with Hsp90 through hydrogen bonding and hydrophobic interactions. Three hydroxy groups on Palmarumycin M2 form hydrogen bonds with Lys58, Gly97, Thr109, Asp102, and Thr152 of Hsp90. Hydrophobic interactions involve Ile96, Phe138, Asn51, Leu107, Thr184, and Val186 of Hsp90 binding to distinct motifs on Palmarumycin M2 (Table 3 and Figure S1). Palmarumycin CE2, a spirodioxynaphthalene compound, is produced by Anteaglonium , a fungal genus belonging to the Anteagloniaceae family within the Pleosporales order [ 55 , 56 ]. Palmarumycin CE2 interacts with Hsp90 through hydrogen bonds and hydrophobic interactions. Its two hydroxy groups form hydrogen bonds with Lys58, Asn51, Ser52, Thr109, Gly97, and Thr152 of Hsp90. Additionally, hydrophobic interactions are facilitated by residues Asn51, Ile96, Phe138, Leu107, Val186, and Thr184, which bind to distinct regions of Palmarumycin CE2, stabilizing the complex and enhancing its binding affinity (Table 3 and Figure S1). Palmarumycin B6, a spirodioxynaphthalene compound, is synthesized by fungi of the genus Berkleasmium , which belongs to the family Dematiaceae [ 57 ]. These fungi are known for producing structurally unique and biologically active secondary metabolites. Palmarumycin B6, with a binding energy of -9.911 kcal/mol, exhibits two distinct modes of hydrogen bond interactions. The first is an intramolecular hydrogen bond between its adjacent hydroxy and carbonyl groups, stabilizing its internal structure. The second is an intermolecular hydrogen bond between the hydroxy group of Palmarumycin B6 and Gly97, Thr184, Thr109, and Lys58 of Hsp90, which is critical in binding to the target protein. Additionally, hydrophobic interactions are enabled by residues, Lys58, Thr184, Asn51, Leu107, and Val186, which bind to distinct regions of Palmarumycin B6, stabilizing the complex and enhancing its binding affinity to Hsp90 (Table 3 and Figure S1). Palmarumycin C13, a spirodioxynaphthalene compound, is produced by fungi of the genus Cladosporium , which encompasses some of the most prevalent indoor and outdoor molds [ 56 ]. Palmarumycin C13, with a binding energy of -9.851 kcal/mol, interacts with Hsp90 through hydrogen bonds and hydrophobic interactions. Specifically, its two hydroxy clusters form hydrogen bonds with Lys58, Gly97, Thr184, and Thr109 of Hsp90. Furthermore, hydrophobic interactions are mediated by residues Lys58, Asn51, Leu107, and Val186, which engage with distinct regions of Palmarumycin C13 (Table 3 and Figure S1). These interactions stabilize the complex and significantly enhance its binding affinity to Hsp90. 3.3.5 Diepoxins subfamily Diepoxins, a unique class of spiroketal-bridged bisepoxides, have been derived from a filamentous fungus such as Berkleasmium sp [ 58 ]. Using NMR spectroscopy-guided structural elucidation, researchers identified these metabolites as spiro-bisnaphthalenes or epoxide-rich derivatives, distinguished by their intricate fused polycyclic frameworks [ 59 ]. This discovery highlights the structural complexity and biosynthetic versatility of fungal secondary metabolites. To date, four diepoxin derivatives have been characterized within this class: diepoxin σ (sigma), diepoxin κ (kappa), diepoxin G, and diepoxin δ (delta) [ 60 ]. Among these, Diepoxine Alpha—a structurally related member sharing the hallmark bisepoxide and spiroketal framework of diepoxins—has been deposited into the PubChem database under the identifier CID 139585239 (entry published on 2021-11-04). In vitro studies have demonstrated that these fungal-derived secondary metabolites exhibit potent cytotoxic, antifungal, and antibiotic activities, suggesting their potential as candidates for therapeutic development [ 61 ]. Molecular docking analysis of these compounds revealed a spectrum of Hsp90 inhibition potential, with calculated ligand binding energies ranging from − 7.512 to -10.348 kcal/mol (Table 2 ), correlating with moderate to potent inhibitory effects. Notably, Diepoxine Alpha (LBE = -10.348 kcal/mol) and Diepoxin σ (sigma) (LBE = -10.200 kcal/mol) exhibited the strongest binding affinities, indicative of robust Hsp90-targeting activity. In contrast, Diepoxin κ (kappa) (-7.512 kcal/mol), Diepoxin G (-8.831 kcal/mol), and Diepoxin δ (delta) (-8.164 kcal/mol) demonstrated comparatively weaker inhibition, underscoring structural variations that modulate efficacy within this compound class. Diepoxin sigma, a spirodioxynaphthalene metabolite of the fungus Neofusicoccum mangiferae , has been reported to possess antifungal and anticancer properties. The proposed Hsp90 inhibitory activity of Diepoxin sigma is attributed to key structural features [ 60 ]. The naphthalene core is predicted to engage in hydrophobic interactions with residues Ala55, Lys58, Gly108, Leu107, Val186, Asn51, and Thr184 of Hsp90. Furthermore, the hydroxy, epoxide (two), and carbonyl (two) substituents on the dioxin ring are predicted to form hydrogen bonds with Lys58, Ile96, Thr109, Gly97, Leu107, Thr152, and Thr184 (Table 3 and Fig. 3 ). Diepoxine Alpha binds to the ATP-binding pocket of Hsp90 via hydrogen bonding and hydrophobic interactions, driven by its spiroketal-bisepoxide structural framework. Specifically, the compound’s carbonyl group forms a hydrogen bond with Lys58, Gly97, Leu107, Ile96, Thr109, Thr184, and Thr152 of Hsp90. Concurrently, hydrophobic interactions are mediated by residues Ala55, Val186, Gly108, and Leu107, which engage with nonpolar regions of Diepoxine Alpha. Notably, Asn51 and Lys58 further stabilize the binding interface through van der Waals contacts, highlighting the synergistic role of polar and nonpolar forces in anchoring the ligand to the chaperone’s active site (Table 3 and Fig. 3 ). 3.3.6 Decaspirone subfamily Decaspirones are a structurally distinct subclass of spirodioxynaphthalenes, closely related to palmarumycins [ 62 , 63 ]. Like their parent compounds, they retain the core spirodioxynaphthalene framework—a naphthalene moiety fused to a decalin system via a spiroketal bridge and two oxygen bridges. However, Decaspirones are characterized by a critical divergence: they incorporate a trans-decalin moiety, in contrast to the cis-decalin stereochemistry feature of palmarumycins. This stereochemical inversion at the decalin ring junction represents the hallmark structural distinction between the two subfamilies, influencing their conformational dynamics and bioactivity [ 63 ]. To date, nine decaspirones (A–I) have been isolated from diverse fungal sources, reflecting distinct ecological niches [ 62 ]. Decaspirones A–E were derived from the freshwater aquatic fungus Decaisnella thyridioides , while Decaspirones F–I were sourced from the saprophytic fungus Helicoma viridis [ 62 , 63 ]. Molecular docking analysis of Decaspirones targeting the Hsp90 ATPase domain revealed significant variability in ligand binding energies, highlighting structure-dependent inhibition (Table 2 ). Decaspirone F exhibited the strongest binding affinity (LBE = -10.016 kcal/mol), followed by Decaspirone G (-9.711 kcal/mol). In comparison, Decaspirone D showed markedly weaker interaction (-7.008 kcal/mol). This gradient in binding efficacy underscores the critical influence of decalin stereochemistry and spiroketal substituents on Hsp90 engagement, positioning Decaspirone F as a lead candidate for therapeutic development. A synergistic interplay of hydrogen bonding and hydrophobic interactions within the ATP-binding pocket drives Decaspirone F’s strong binding affinity to Hsp90. The compound’s hydroxy groups form critical hydrogen bonds with residues Lys58, Asn51, Glu74, Gly135, Thr184, and Thr152, while its hydrophobic regions engage residues Leu107, Phe138, Thr184, Gly108, and Val186 through van der Waals contacts. Notably, Asn51 and Lys58 participate in both interaction types, stabilizing the ligand’s orientation (Table 3 and Fig. 3 ). This dual binding mechanism, anchored to conserved regions of Hsp90’s catalytic domain, underscores Decaspirone F’s structural complementarity and potent inhibitory potential. Decaspirone G exhibited a moderately strong binding affinity to Hsp90’s ATP-binding pocket (LBE = -9.711 kcal/mol), driven by a synergistic interplay of hydrogen bonding and hydrophobic interactions. Lys58, Gly97, Thr184, and Thr109 of Hsp90 are engaged with hydrogen bonds with polar parts of Decaspirone G. Hydrophobic contacts with Lys58, Asn51, Leu107, Phe138, and Met98 further anchored the ligand to conserved regions of the catalytic domain (Table 3 and Figure S1). This cooperative binding mechanism compensates for its slightly weaker affinity than Decaspirone F (LBE = -10.016 kcal/mol), underscoring the structural adaptability of spirodioxynaphthalenes in targeting Hsp90’s functional epitopes. 3.3.7 Rhytidone and Rhytidenone subfamily Rhytidone and Rhytidenone are structurally related subgroups within the spirodioxynaphthalene family, distinguished by their decalin-derived modifications and distinct fungal origins [ 64 ]. Both compounds share a core spirodioxynaphthalene framework, where a naphthalene moiety is fused to a decalin system via a spiroketal bridge stabilized by oxygen linkages. The key divergence lies in their decalin substituents: Rhytidone features a cis-decalin moiety bearing a carbonyl group (e.g., ketone). Rhytidenone incorporates a trans-decalin moiety with a carbonyl group and at least one alkene, enhancing conformational rigidity and bioactivity. To date, three spirodioxynaphthalene (Rhytidone A–C) and eight rhytidenones (A–H) have been characterized. Rhytidenones have been evaluated for their anticancer potential, with Rhytidenone F emerging as the most potent cytotoxic agent [ 64 ]. Other derivatives, such as Rhytidenones B–E, exhibit broad-spectrum antimicrobial properties, including antifungal and antibacterial activities [ 65 ]. In parallel, Rhytidone A was assessed for cytotoxicity against human Ramos cells using the Cell Titer-Glo assay after 24-hour exposure [ 64 , 65 ]. While initial testing revealed a reduction in cell viability, the activity outcomes remain inconclusive. Molecular docking analysis revealed that Rhytidenone subclasses engage Hsp90 with varying binding affinities. Rhytidenone F exhibited the strongest binding mode (LBE = -9.688 kcal/mol), whereas Rhytidenones A and H bound poorly (LBE = -2.696 and − 6.784 kcal/mol, respectively; Table 2 ). Rhytidenones B, C, D, E, and G showed moderate binding affinity (LBE values of -9.283, -9.410, -9.424, -9.456, and − 9.320 kcal/mol, respectively), Table 2 . Within the ATP binding pocket of Hsp90, Rhytidenone F interacts with Lys58, Gly97, Thr184, and Thr109 via hydrogen bonds, and with Lys58, Asn51, and Phe138 through hydrophobic contacts (Table 3 and Figure S1). On the other side, the Rhytidone series (A–C), with moderate binding affinities (-9.023 to -8.986 kcal/mol), underperforms compared to most Rhytidenones (Table 2 ). This disparity may stem from structural distinctions, such as the absence of alkene groups or reliance on cis -decalin configurations, which reduce conformational rigidity and limit hydrophobic engagement. 3.3.8 Guignardin subfamily Guignardins are a family of bioactive spirodioxynaphthalenes, complex polycyclic secondary metabolites primarily isolated from endophytic fungi, especially Guignardia species [ 66 ]. Their defining structural feature is a spirobisnaphthalene core, formed by two naphthalene units linked via a spiroketal bridge stabilized by two oxygen atoms. Individual guignardins (A-F) are distinguished by their substituents and stereochemistry variations. The primary source of guignardins is the endophytic fungus Guignardia sp. KcF8 is isolated from plants such as Dioscorea zingiberensis [ 66 , 67 ]. These compounds have also been found in fungi associated with mangroves and terrestrial environments. Guignardins possess promising pharmacological properties, including enzymatic inhibition, antifungal activity, and cytotoxicity [ 66 ]. Consequently, they are being investigated for potential therapeutic applications in diabetes, cancer, and inflammation based on their ability to modulate enzyme activity. Molecular docking analysis demonstrated that guignardins bind to the ATP-binding pocket of Hsp90 with distinct interaction profiles and varying affinities. Among these, Guignardin B (LBE = -10.263 kcal/mol) and Guignardin F (LBE = -9.657 kcal/mol) exhibited the most potent binding, driven by complementary interactions with conserved residues in the catalytic domain (Table 2 ). Guignardin B forms hydrogen bonds with Lys58, Leu48, Asn51, Gly97, Thr184, and Thr109 of Hsp90, while hydrophobic contacts with Lys58, Asn51, Ala55, Val186, and Leu107 stabilize its positioning (Table 3 and Fig. 3 ). Notably, Lys58 and Asn51 participate in polar and nonpolar interactions, underscoring their dual role in ligand anchoring. Guignardin F engages with Lys58, Gly97, and Thr184 of Hsp90 via hydrogen bonds interaction and relies on hydrophobic interactions with Lys58, Asn51, and Leu107, Phe138, Thr184, and Asp93 to secure its binding (Table 3 and Figure S1). The robust affinities of Guignardin B and F highlight their potential to competitively inhibit ATP hydrolysis, disrupting Hsp90's chaperone function and offering a pathway for cancer therapy. Guignardin D (LBE = -7.033 kcal/mol) exhibits weak binding affinity to Hsp90, likely due to steric and electronic incompatibilities arising from its structural features. The acetal moiety introduces steric bulk, disrupting optimal positioning within the ATP-binding pocket. At the same time, the carboxylic acid group may destabilize hydrophobic interactions or induce unfavorable electrostatic repulsion with adjacent residues (e.g., Lys58 or Thr184). This dual interference underscores functional group optimization's importance in enhancing binding efficacy in future analogs. 3.3.9 Cladospirone subfamily Cladospirones represent a structurally distinct subgroup within the spirobisnaphthalene family, closely related to palmarumycins [ 56 , 57 ]. While retaining the core spirobisnaphthalene framework—comprising a naphthalene moiety fused to a decalin system via a spiroketal bridge and dual oxygen bridges—Cladospirones are defined by a critical structural divergence: the presence of a β-hydroxy group at the C-8a position, contrasting sharply with the cis-decalin stereochemistry characteristic of palmarumycins. This stereochemical inversion at the decalin ring junction is the hallmark distinction between the two subfamilies, profoundly influencing their conformational flexibility, molecular interactions, and bioactivity profiles. To date, nine Cladospirone derivatives have been identified within the spirobisnaphthalene family. The inaugural member, Cladospirone bisepoxide (Cladospirone A), was first isolated in 1994 from the fungus Sphaeropsidales sp., distinguished by its spiroketal-bridged bisepoxide framework [ 67 , 68 ]. Subsequent research in 2000 expanded this family with the discovery of Cladospirones B–I from Sphaeropsidales sp. F-24′707 under optimized fermentation conditions [ 68 , 69 ]. These derivatives showcase remarkable structural diversity, driven by hydroxylation patterns, stereochemical permutations, and oxygen bridge modifications, underscoring the biosynthetic versatility of their fungal producers. Cladospirones, due to their unique structural properties, exhibit a range of bioactivities, including antimicrobial, anticancer, and enzyme modulation effects. Molecular docking studies indicate moderate binding affinities of these compounds toward the Hsp90 ATPase binding pocket (Table 2 ). Cladospirone bisepoxide (-9.556 kcal/mol) and Cladospirone D (-9.397 kcal/mol) exhibited the most potent binding affinities within this group, likely due to their spirobisnaphthalene structural motifs. Cladospirone bisepoxide forms multiple hydrogen bonds with key Hsp90 residues, including Lys58, Gly97, Thr152, Thr184, and Gly135. Hydrophobic interactions with Asn51, Lys58, Leu107, and Val186 further contribute to its stability within the binding pocket (Table 3 , Figure S1). 3.3.10 Ascochytatin subfamily Ascochytatin is a bioactive spirodioxynaphthalene metabolite isolated from the marine-derived fungus Ascochyta sp. NGB4. First identified in 2008, this compound features a spirobisnaphthalene scaffold—a structural hallmark of its class—comprising fused naphthalene moieties interconnected via a spiroketal bridge [ 70 ]. Distinctively, Ascochytatin’s core structure is further substituted with an epoxy ring and three hydroxy groups, enhancing its bioactivity. These functional groups contribute to its antimicrobial potential, enzyme modulation effects, and cytotoxic properties, positioning it as a promising candidate for therapeutic development. Molecular docking simulations of Ascochytatin, the sole characterized member of its family, revealed a moderate binding affinity (LBE = -7.948 kcal/mol) against Hsp90. The interaction is stabilized by a synergistic interplay of H-bonds with catalytic residues (e.g., Lys58, Gly97, Thr109, Thr152, Thr184, and Phe138), hydrophobic contacts within the ATP-binding pocket (e.g., Asn51, Gly97, Thr184, Leu107, Thr109, Val136, Phe138 ), and ion-π interactions involving aromatic moieties and Lys58 (Table 3 , Figure S1). 3.3.11 Miscellaneous spirodioxynaphthalenes In addition to the subfamilies of spirodioxynaphthalenes, a group of compounds that did not belong to the previously mentioned categories was identified within natural product databases (Table 2 ). These compounds, which feature a spirodioxynaphthalene structure, underwent molecular docking analysis to evaluate their potential activity in modulating Hsp90. Based on their docking score these compounds have shown weak to strong binding potential against Hsp90 (Table 3 ). Sch53514 (LBE = -10.109 kcal/mol) and compound CID: 156020160 (-9.748 kcal/mol) show the strongest binding affinity, making them the most promising candidates for Hsp90 inhibition. These spirodioxynaphthalenes likely have highly favorable interactions with the Hsp90 active site, driven by hydrogen bonding and hydrophobic contacts. The Sch53514 chemical structure analysis revealed that this molecule is like the cladospirone subfamily. This is evident by its shared structural features, including a naphthalene moiety fused to a decalin system through a spiroketal bridge, two oxygen bridges, and a β-hydroxy group at the C-8a position. The compound with CID 156020160 is a spirobisnaphthalene derivative with structural features of a tricyclic tridecane core with a spirocyclic connection to a cyclohexene ring. The molecule also incorporates oxygen-containing functional groups: a carbonyl at position 1, a hydroxy group at position 6', and a methoxy group at position 3'. Both molecules interact with Hsp90 through a combination of hydrophobic and H-bond interactions. Sch53514 interacts with Lys58, Gly97, Thr184, Thr109, and Thr152 of Hsp90 through hydrogen bonds, while Lys58, Val186, Leu107, Ala55, Gly108, Asn51, Thr184, Lys58 of Hsp90 engage in hydrophobic interactions with various motifs of Sch53514 (Table 3 and Fig. 3 ). 3.4 Mode of binding verification Lys58, Gly97, and Thr184 frequently interact with spirodioxynaphthalene derivatives and the Hsp90 NTD (Table 4 ). Lys58 is the most frequently involved residue in H-bonding, appearing in all 20 cases (100%). This highlights its critical role in stabilizing ligand binding. Gly97 and Thr184 also significantly contribute to hydrogen bonding, appearing in 80% and 75% of cases, suggesting that these residues are key mediators of ligand-protein interactions. Thr109 and Asn51 further support ligand binding through hydrogen bonds but with lower frequency, appearing in 65% and 30% of cases. Hydrophobic interactions play a crucial role in stabilizing the binding of ligands within the ATP-binding pocket. Key residues Thr184, Leu107, and Lys58 are each involved in 65% of observed hydrophobic interactions, highlighting their significant contribution to nonpolar binding. Asn51 (60%) and Val186 (40%) also play notable roles, further stabilizing the ligand within the pocket. Additional residues, including Ile96, Ala55, and Phe138, contribute to hydrophobic stabilization with a lower frequency of 30% each. These findings suggest a network of hydrophobic contacts working in concert to secure the ligand within the Hsp90 protein. Ion-π interactions appear to play a negligible role, with Lys58 showing three occurrences with 100% overall contribution. The obtained data suggests that targeted mutagenesis of Lys58, Thr184, or Gly97 could significantly impact ligand binding, making them key residues for experimental validation in drug discovery efforts. To further investigate the roles of these residues, we performed molecular docking studies using Hsp90 NTD mutants. Specifically, we generated Lys58Ala, Thr184Ala, Gly97Ala, Lys58/Thr184Ala, and Lys58/Gly97/Thr184Ala mutants (PDB ID: 6LTT) using PyMOL 2.1. This approach allowed us to assess the impact of these mutations on ligand binding. Table 4 Frequency and Percentage of Key Hsp90 NTD Residues Involved in Spirodioxynaphthalene Derivative Binding Across Different Interaction Types Amino Acid H-Bond Hydrophobic Ion-π Count Percentage Count Percentage Count Percentage Lys58 20 100% 12 60% 3 1000% Gly97 16 80% 1 5% 0 0% Thr184 15 75% 13 65% 0 0% Thr109 13 65% 1 5% 0 0% Asn51 6 30% 12 60% 0 0% Leu107 6 30% 13 65% 0 0% Thr152 6 30% 0 0% 0 0% Ile96 3 15% 6 30% 0 0% Ala55 0 0% 6 30% 0 0% Phe138 1 5% 7 35% 0 0% Val186 0 0% 8 40% 0 0% Gly108 2 10% 5 25% 0 0% Gly135 2 10% 0 0% 0 0% Ser52 1 5% 0 0% 0 0% Glu74 1 5% 0 0% 0 0% Asp102 1 5% 0 0% 0 0% Leu48 1 5% 0 0% 0 0% Asp93 0 0% 1 5% 0 0% Met98 0 0% 1 5% 0 0% Val136 0 0% 1 5% 0 0% Analysis of docking results revealed that mutations generally reduced the binding affinity of spirodioxynaphthalene derivatives to Hsp90 NTD (Table 5 ). The extent to which binding affinity is affected differs across compounds and depending on the specific mutation(s). The Lys58 to Ala mutation significantly reduced binding affinity for several compounds, highlighting the importance of Lys58 in ligand binding. Notable reductions include Decaspirone F (-1.905 kcal/mol), Palmarumycin M2 (-1.257 kcal/mol), Palmarumycin CE2 (-0.802 kcal/mol), and Preussomerin D (-0.635 kcal/mol). These findings support the established role of Lys58 in hydrophobic, hydrogen bond, and ion-pi interactions with ligands. However, Preussomerin E exhibited a slight increase in binding affinity (0.059 kcal/mol) upon mutation, suggesting that the introduced mutation may induce a conformational change that enhances binding for this specific ligand. Thr184 to Ala mutation had a variable effect, sometimes slightly increasing binding (e.g., Preussomerin E), the combined Lys58 & Thr184 to Ala mutation predictably resulted in the largest decrease in binding affinity. The Gly97 to Ala mutation had a diverse influence on the binding affinity of spirodioxynaphthalene derivatives to Hsp90 NTD. A subset of compounds (Decaspirone F, Preussomerin B, Preussomerin D, Palmarumycin M2, Palmarumycin CE2, and Diepoxine Sigma) exhibited a reduction in binding affinity upon mutation, with Decaspirone F showing the most significant decrease (-1.536 kcal/mol). Conversely, another group of compounds (Sparticolin G, Preussomerin E, Anteaglonialide E, Anteaglonialide F, Guignardin B, Diepoxine Alpha, and Sch53514) showed a slight increase in binding affinity. These contrasting effects indicate that the mutation does not uniformly impact all ligands, suggesting that spirodioxynaphthalene derivatives interact with the Hsp90 NTD through distinct binding mechanisms. The impact of multiple points mutations on the binding affinity of spirodioxynaphthalene derivatives to Hsp90 NTD was investigated. Both the double mutation (Lys58 and Thr184 to Ala) and the triple mutation (Lys58, Gly97, and Thr184 to Ala) consistently reduced binding affinity across all tested compounds, underscoring the crucial role of these residues in stabilizing protein-ligand interactions. The most prominent reductions in binding affinity were observed for Decaspirone F (-1.723 kcal/mol for the double mutation and − 1.726 kcal/mol for the triple mutation), Palmarumycin M2 (-1.433 kcal/mol and − 1.412 kcal/mol, respectively), and Palmarumycin CE2 (-1.03 kcal/mol and − 1.018 kcal/mol, respectively). The consistent and substantial decrease in binding affinity with the triple mutation suggests that Lys58, Gly97, and Thr184 act synergistically to create a critical interaction hotspot (e.g., hydrophobic and hydrogen bond interactions) that are essential for stabilizing the binding of these derivatives to Hsp90 NTD. Table 5 Impact of in-silico mutations on the binding affinity of spirodioxynaphthalene derivatives to Hsp90’NTD Compound WT Hsp90’ NTD LBE (kcal/mol) Mutated Hsp90’s NTD Lys58→Ala (kcal/mol) Gly97→Ala (kcal/mol) Thr184→Ala (kcal/mol) Lys58 & Thr184→Ala (kcal/mol) Lys58, Gly97, & Thr184→Ala (kcal/mol) Sparticolin G -10.636 -10.217 -10.741 -10.431 -9.909 -9.918 Preussomerin B -10.417 -9.870 -10.060 -9.738 -9.591 -9.605 Preussomerin D -10.165 -9.530 -9.986 -9.712 -9.285 -9.344 Preussomerin E -10.088 -10.147 -10.095 -9.760 -9.928 -9.936 Palmarumycin M2 -10.134 -8.877 -9.440 -9.230 -8.701 -8.722 Palmarumycin CE2 -10.021 -9.219 -9.472 -9.176 -8.991 -9.003 Anteaglonialide E -10.141 -9.724 -10.145 -9.902 -9.453 -9.473 Anteaglonialide F -10.179 -9.667 -10.218 -9.917 -9.368 -9.390 Guignardin B -10.263 -9.967 -10.274 -9.960 -9.557 -9.546 Diepoxine Alpha -10.348 -9.928 -10.354 -10.039 -9.629 -9.618 Diepoxine Sigma -10.200 -9.980 -9.813 -9.651 -9.509 -9.751 Decaspirone F -10.016 -8.111 -8.480 -8.304 -8.284 -8.290 Sch53514 -10.109 -9.549 -10.129 -9.806 -9.262 -9.272 3.5 Spirodioxynaphthalenes physicochemical, pharmacokinetics, drug-likeness, and medicinal chemistry properties assessment The physicochemical properties of the top-ranked spirodioxynaphthalenes derivatives were evaluated to assess their drug-likeness and potential for therapeutic applications (Table 6 and Table 7 ). These molecules have a molecular weight (MW) range of 320.3–368.34 g/mol. All compounds fall within the optimal range for drug-like molecules (typically < 500 Da), which agrees with Lipinski RO5 and indicates good potential for cell permeability and oral bioavailability. The spirodioxynaphthalene molecules demonstrate limited rotatable bonds (0–1), indicating a rigid conformation crucial for binding specificity to Hsp90. The number of hydrogen bond acceptors ranges from 5 to 7, while hydrogen bond donors range from 0 to 3. These values are acceptable for drug-like molecules, suggesting favorable interactions with the Hsp90's NTD. Topological Polar Surface Area (TPSA) quantifies the polar surface area of a molecule, calculated as the sum of surface areas contributed by oxygen, nitrogen, and their attached hydrogen atoms. Optimal TPSA values are context-dependent, influenced by factors such as the molecule's target site, administration route, and therapeutic class. For instance, anticancer agents often exhibit acceptable TPSA values between 70–120 Ų, while orally available drugs typically fall within 60–100 Ų. The top-ranked spirodioxynaphthalenes showed TPSA values ranging from 61.83–101.05 Ų, suggesting favorable drug-like properties, particularly for oral administration, and demonstrating good potential as anticancer agents. ESOL (Estimated Solubility) is a computational model that predicts the aqueous solubility of a compound based on its molecular properties. ESOL provides two key values: ESOL Log S, which reflects solubility in mol/L (higher Log S values indicate more excellent solubility), and ESOL solubility (mg/mL), representing the estimated concentration in water. Regarding Log S, compounds with values > -2.0 are considered highly soluble, moderately soluble between − 2.0 and − 4.0, and those < -4.0 are poorly soluble. The top-ranked spirodioxynaphthalenes derivatives have ESOL Log S) ranging from − 4.09 (for Sparticolin G) to -2.67 ( for Sch53514), suggesting soluble to mode moderately soluble molecules. Table 6 In-silico prediction of the physicochemical properties of the top-ranked spirodioxynaphthalenes Molecule Formula MW (g/mol) #RB #HBA #HBD TPSA (Ų) ESOL Log S ESOL Solubility (mg/ml) ESOL Class Sparticolin G C 19 H 12 O 5 320.3 0 5 0 61.83 -4.09 2.62E-02 Moderately soluble Preussomerin B C 20 H 16 O 7 368.34 0 7 3 100.91 -2.72 6.96E-01 Soluble Preussomerin D C 20 H 12 O 7 364.31 0 7 2 97.75 -2.96 4.02E-01 Soluble Preussomerin E C 20 H 12 O 7 364.31 0 7 2 97.75 -3.49 1.19E-01 Soluble Palmarumycin M2 C 20 H 20 O 6 356.37 0 6 3 96.22 -3.12 2.69E-01 Soluble Palmarumycin CE2 C 20 H 20 O 5 340.37 0 5 2 75.99 -3.64 7.71E-02 Soluble Anteaglonialide E C 20 H 18 O 5 338.35 1 5 0 61.83 -4.03 3.14E-02 Moderately soluble Anteaglonialide F C 20 H 16 O 5 336.34 1 5 0 61.83 -4.03 3.17E-02 Moderately soluble Guignardin B C 20 H 14 O 5 334.32 0 5 2 71.45 -4.06 2.90E-02 Moderately soluble Diepoxine Alpha C 20 H 14 O 7 366.32 0 7 1 97.89 -2.94 4.21E-01 Soluble Diepoxine Sigma C 20 H 12 O 7 364.31 0 7 1 97.89 -2.93 4.31E-01 Soluble Decaspirone F C 20 H 18 O 5 338.35 0 5 3 79.15 -3.41 1.31E-01 Soluble Sch53514 C 20 H 14 O 7 366.32 0 7 2 101.05 -2.67 7.85E-01 Soluble The spirodioxynaphthalene derivatives exhibited favorable drug-likeness properties, as determined by Lipinski's Rule of Five, Ghose, Veber, Egan, and Muegge filters, bioavailability score, lead-likeness violations, and synthetic accessibility (Table 7 ). All spirodioxynaphthalene derivatives analyzed comply with Lipinski's Rule of Five, indicating favorable absorption and permeability profiles. Additionally, consistent with the favorable physicochemical properties observed in Table 6 , all spirodioxynaphthalene derivatives meet the Ghose, Veber, Egan, and Muegge criteria, solidifying their potential as drug-like candidates. Based on computational predictions, all molecules have a Bioavailability Score of 0.55, suggesting a 55% probability of successful oral absorption in humans. Most spirodioxynaphthalene derivatives demonstrate 0 or 1 lead-likeness violation, signifying desirable characteristics for lead compounds in drug discovery. Compounds with a single violation (Preussomerin B/D/E, Palmarumycin M2, Diepoxine Alpha/Sigma, Sch53514) might require minor structural adjustments for improved lead-likeness. Finally, the Synthetic Accessibility (SA) Score, a computational metric for estimating the ease of chemical synthesis, ranges from 1 (very easy) to 10 (very difficult). The SA scores for these molecules fall between 4.24 and 5.78, suggesting a moderate level of synthetic complexity suitable for drug development. Collectively, Sparticolin G, Anteaglonialide E/F, and Guignardin B stand out as the most promising candidates due to their excellent drug-likeness profiles, including zero lead-likeness violations, good bioavailability, and more straightforward synthesis. Although Sch53514, Preussomerin B, and Diepoxine Sigma may require more complex synthetic routes, they remain viable candidates with favorable drug-like properties. All compounds warrant further optimization and preclinical studies. Table 7 In-silico prediction of the drug-likeness of the top-ranked spirodioxynaphthalenes based on Lipinski, Veber, Ghose, Egan rules, and Muegge filters, bioavailability score, lead-likeness violations, and synthetic accessibility. Molecule Lipinski #violations Ghose #violations Veber #violations Egan #violations Muegge #violations Bioavailability Score Lead likeness #violations Synthetic Accessibility Sparticolin G 0 0 0 0 0 0.55 0 4.60 Preussomerin B 0 0 0 0 0 0.55 1 5.68 Preussomerin D 0 0 0 0 0 0.55 1 5.54 Preussomerin E 0 0 0 0 0 0.55 1 5.54 Palmarumycin M2 0 0 0 0 0 0.55 1 4.99 Palmarumycin CE2 0 0 0 0 0 0.55 0 4.75 Anteaglonialide E 0 0 0 0 0 0.55 0 4.24 Anteaglonialide F 0 0 0 0 0 0.55 0 4.43 Guignardin B 0 0 0 0 0 0.55 0 4.78 Diepoxine Alpha 0 0 0 0 0 0.55 1 5.43 Diepoxine Sigma 0 0 0 0 0 0.55 1 5.66 Decaspirone F 0 0 0 0 0 0.55 0 5.12 Sch53514 0 0 0 0 0 0.55 1 5.78 3.6 Cytotoxicity Prediction CLC-Pred (Cell Line Cytotoxicity Predictor), a web-based platform, predicts compound cytotoxicity in normal and cancerous cell lines using structural formulas as input. This in-silico approach employs QSAR models trained on experimental cytotoxicity data [ 43 ]. We used CLC-Pred 2.0 ( https://www.way2drug.com/Cell-line ) with SMILES representations to predict the potential anticancer activity of the selected top-ranked spirodioxynaphthalenes (Table 8 ). The in-silico analysis using CLC-Pred reveals potential anticancer activity for several spirodioxynaphthalene derivatives. Guignardin B, Diepoxine Alpha, Diepoxine Sigma, and Sch53514 stand out with exceptionally high predicted probabilities of activity (Pa values approaching 1.0) against both MDA-MB-231 (breast adenocarcinoma) and MCF 7.00 (breast carcinoma) cell lines, indicating potent potential cytotoxicity. Preussomerin D and E also exhibit high predicted activity, particularly in MCF 7.00 cells. Guignardin B demonstrates a broader potential, showing activity against breast cancer and renal carcinoma (RXF 393). Several compounds exhibit varied activity across cell lines, suggesting potential cell-type selectivity. For instance, Palmarumycin M2 shows moderate predicted activity against melanoma (M19-MEL) and pancreatic cancer (CFPAC-1). Decaspirone F and Anteaglonialide F show modest predicted activity against brain (Hs 683) and colon (DLD-1) cancers, respectively. Anteaglonialide E exhibits the lowest predicted activity against colon cancer. Palmarumycin CE2 and Anteaglonialide F show lower predicted efficacy in breast cancer than other tested compounds. Table 8 CLC-Pred Cytotoxicity Predictions for Spirodioxynaphthalenes Compound Pa * Pi ** Cell-line Cell-line name Tissue/organ Sparticolin G 0.870 0.004 MDA-MB-231 Breast adenocarcinoma Breast 0.841 0.008 MCF 7.00 Breast carcinoma Breast Preussomerin B 0.798 0.011 MCF 7.00 Breast carcinoma Breast Preussomerin D 0.914 0.005 MCF 7.00 Breast carcinoma Breast 0.718 0.006 MDA-MB-231 Breast adenocarcinoma Breast Preussomerin E 0.942 0.005 MCF 7.00 Breast carcinoma Breast 0.773 0.005 MDA-MB-231 Breast adenocarcinoma Breast Palmarumycin M2 0.748 0.002 M19-MEL Melanoma Skin 0.753 0.014 MCF 7.00 Breast carcinoma Breast 0.679 0.003 CFPAC-1 Pancreatic carcinoma Pancreas Palmarumycin CE2 0.698 0.020 MCF 7.00 Breast carcinoma Breast Anteaglonialide E 0.565 0.004 DLD-1 Colon adenocarcinoma Colon Anteaglonialide F 0.696 0.007 MDA-MB-231 Breast adenocarcinoma Breast 0.608 0.031 MCF 7.00 Breast carcinoma Breast Guignardin B 0.914 0.005 MCF 7.00 Breast carcinoma Breast 0.906 0.004 MDA-MB-231 Breast adenocarcinoma Breast 0.833 0.004 RXF 393 Renal carcinoma Kidney 0.688 0.013 PC-6 Small cell lung carcinoma Lung 0.637 0.005 MDA-MB-468 Breast adenocarcinoma Breast Diepoxine Alpha 0.995 0.003 MDA-MB-231 Breast adenocarcinoma Breast 0.993 0.004 MCF 7.00 Breast carcinoma Breast Diepoxine Sigma 0.993 0.003 MDA-MB-231 Breast adenocarcinoma Breast 0.993 0.004 MCF 7.00 Breast carcinoma Breast Decaspirone F 0.831 0.009 MCF 7.00 Breast carcinoma Breast 0.779 0.005 MDA-MB-231 Breast adenocarcinoma Breast 0.681 0.012 Hs 683 Oligodendroglioma Brain Sch53514 0.996 0.002 MDA-MB-231 Breast adenocarcinoma Breast 0.995 0.003 MCF 7.00 Breast carcinoma Breast * Pa: Probability of Activity ** Pi: Probability of Inactivity 4. Conclusion and future direction Hsp90 is a critical molecular chaperone accountable for appropriately folding and functioning considerable client proteins implicated in life-threatening diseases, including cancer. Consequently, targeting Hsp90 activity offers a promising therapeutic strategy. Spirodioxynaphthalenes are expanding fungal secondary metabolites with largely unexplored biological activities. This report aims to specify spirodioxynaphthalene-derivatives as potential inhibitors of Hsp90 activity. Using integrated computer-aided drug discovery pipelines, we identified thirteen spirodioxynaphthalenes from natural product databases promising inhibitors against Hsp90 activity as an initial step in novel drug development. All these compounds exhibit favorable drug-like properties, promising pharmacokinetic profiles, and cytotoxic potential. Their strong binding affinities, ranging from − 10.016 to -10.636 kcal/mol, highlight their potential for further optimization. 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RSC Adv 7:48031–48038 Singh SB, Zink DL, Liesch JM, Ball RG, Goetz MA, Bolessa EA, Giacobbe RA, Silverman KC, Bills GF (1994) Preussomerins and Deoxypreussomerins: Novel Inhibitors of Ras Farnesyl-Protein Transferase. J Org Chem 59:6296–6302 Chen S, Chen D, Cai R, Cui H, Long Y, Lu Y, Li C, She Z (2016) Cytotoxic and Antibacterial Preussomerins from the Mangrove Endophytic Fungus Lasiodiplodia theobromae ZJ-HQ1. J Nat Prod 79:2397–2402 Xu Y, Mafezoli J, Oliveira MCF, U’Ren JM, Arnold AE, Gunatilaka AAL (2015) Anteaglonialides A–F and Palmarumycins CE 1 –CE 3 from Anteaglonium sp. FL0768, a Fungal Endophyte of the Spikemoss Selaginella arenicola . J Nat Prod 78:2738–2747 Li Y, Shan T, Mou Y, Li P, Zhao J, Zhao W, Peng Y, Zhou L, Ding C (2012) Enhancement of Palmarumycin C12 and C13 Production in Liquid Culture of the Endophytic Fungus Berkleasmium sp. Dzf12 by Oligosaccharides from Its Host Plant Dioscorea zingiberensis. Molecules 17:3761–3773 Bunyapaiboonsri T, Yoiprommarat S, Nopgason R, Intereya K, Suvannakad R, Sakayaroj J (2015) Palmarumycins from the mangrove fungus BCC 25093. Tetrahedron 71:5572–5578 Liu X, Wang W, Zhao Y, Lai D, Zhou L, Liu Z, Wang M (2018) Total Synthesis and Structure Revision of Palmarumycin B 6 . J Nat Prod 81:1803–1809 Shan T, Tian J, Wang X, Mou Y, Mao Z, Lai D, Dai J, Peng Y, Zhou L, Wang M (2014) Bioactive Spirobisnaphthalenes from the Endophytic Fungus Berkleasmium sp. J Nat Prod 77:2151–2160 Wipf P, Jung J-K (2000) Formal Total Synthesis of (+)-Diepoxin σ. J Org Chem 65:6319–6337 Schlingmann G, West RR, Milne L, Pearce CJ, Carter GT (1993) Diepoxins, novel fungal metabolites with antibiotic activity. Tetrahedron Lett 34:7225–7228 Gocer H, Aslan A, Gülçin İ, Supuran CT (2015) Spirobisnaphthalenes effectively inhibit carbonic anhydrase. J Enzyme Inhib Med Chem 1–5 Hu H, Guo H, Li E, Liu X, Zhou Y, Che Y (2006) Decaspirones F – I, Bioactive Secondary Metabolites from the Saprophytic Fungus Helicoma viridis. J Nat Prod 69:1672–1675 Jiao P, Swenson DC, Gloer JB, Campbell J, Shearer CA (2006) Decaspirones A – E, Bioactive Spirodioxynaphthalenes from the Freshwater Aquatic Fungus Decaisnella thyridioides. J Nat Prod 69:1667–1671 Yue Z, Lam HC, Chen K, Siridechakorn I, Liu Y, Pudhom K, Lei X (2020) Biomimetic Synthesis of Rhytidenone A and Mode of Action of Cytotoxic Rhytidenone F. Angew Chem Int Ed 59:4115–4120 Pudhom K, Teerawatananond T (2014) Rhytidenones A–F, Spirobisnaphthalenes from Rhytidhysteron sp. AS21B, an Endophytic Fungus. J Nat Prod 77:1962–1966 Ai W, Wei X, Lin X, Sheng L, Wang Z, Tu Z, Yang X, Zhou X, Li J, Liu Y (2015) ChemInform Abstract: Guignardins A—F, Spirodioxynaphthalenes from the Endophytic Fungus Guignardia sp. KcF8 as a New Class of PTP1B and SIRT1 Inhibitors. https://doi.org/10.1002/chin.201505211 . ChemInform Cadamuro RD, da Silveira Bastos IMA, Silva IT et al (2021) Bioactive Compounds from Mangrove Endophytic Fungus and Their Uses for Microorganism Control. J Fungi 7:455 Bode HB, Walker M, Zeeck A (2000) Cladospirones B to I from Sphaeropsidales sp. F-24′707 by Variation of Culture Conditions. Eur J Org Chem 2000:3185–3193 WEGNER BODEHB B, ZEECK A (2000) Biosynthesis of Cladospirone Bisepoxide, A Member of the Spirobisnaphthalene Family. J Antibiot (Tokyo) 53:153–157 Kanoh K, Okada A, Adachi K, Imagawa H, Nishizawa M, Matsuda S, Shizuri Y, Utsumi R (2008) Ascochytatin, a Novel Bioactive Spirodioxynaphthalene Metabolite Produced by the Marine-derived Fungus, Ascochyta sp. NGB4. J Antibiot (Tokyo) 61:142–148 Additional Declarations The authors declare no competing interests. Supplementary Files FigS1.tiff Fig S1 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6199117","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":426965159,"identity":"5985e7e3-47c2-468b-bc38-e99843fe180b","order_by":0,"name":"Adam Aboalroub","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYFCCBAYGxgYGfn4wu4AELZIzG0BsA1K0bDgA4hCjhb89+ekGxh21EsbnVyd+eGDAIM8vdgC/Fokzz8xuMJ45LmF24+1mCaDDDGfOTiBgzY0EoJa2Y3VmN85uAGlJMLhNQIv8jfRvIC0SxjPObv5BlBaDGzkgW2okDPh7txFni+GZN2U3EtsOSEjc4N1mkWAgQdgvcsfTt9342FYnwd9/dvPNHxU28vzSBLSAQQLDYWDYgVVKEKEcAuqAMXSAaNWjYBSMglEwwgAAZR5K60McW9kAAAAASUVORK5CYII=","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Adam","middleName":"","lastName":"Aboalroub","suffix":""}],"badges":[],"createdAt":"2025-03-11 01:06:26","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6199117/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6199117/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78334270,"identity":"dd921dec-8ad2-4c31-b9f2-eec568f0965f","added_by":"auto","created_at":"2025-03-12 07:42:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":91610,"visible":true,"origin":"","legend":"\u003cp\u003eChemical Structures of Spirodioxynaphthalene Derivatives Exhibiting Strong Binding Affinity to Hsp90\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6199117/v1/fa41503b8c42cbdc5cec768e.png"},{"id":78334643,"identity":"fbcccec1-e5ad-4fb2-823a-1bdd069ea2e9","added_by":"auto","created_at":"2025-03-12 07:50:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":59667,"visible":true,"origin":"","legend":"\u003cp\u003eDocking poses of ATP (A) and top-ranked spirodioxynaphthalenes (B) in the Hsp90 NTD ATP-binding pocket (PDB: 6LTI). Key interactions are shown for ATP (C): hydrogen bonds (green), hydrophobic contacts (red).\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6199117/v1/ebf8a1efbc21690d9e41174b.png"},{"id":78334272,"identity":"1db59079-f65f-47a4-aa7e-79223da9d6d3","added_by":"auto","created_at":"2025-03-12 07:42:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":121637,"visible":true,"origin":"","legend":"\u003cp\u003eStick representation of the top six ranked compounds docked into the ATP-binding pocket of the Human Hsp90 N-terminal domain (PDB ID: 6LTI), illustrating hydrogen bonds (green dashed lines) and hydrophobic interactions (red dashed lines).\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6199117/v1/ef07f2a81afb828394cf157a.png"},{"id":78334274,"identity":"1ffd4cda-0684-4617-8332-e26cadb6439a","added_by":"auto","created_at":"2025-03-12 07:42:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":31983,"visible":true,"origin":"","legend":"\u003cp\u003eStick representation showing the ion-pi interaction (yellow dashed lines) between Lys58 and Sparticolin G, Anteaglonialide F, and Anteaglonialide E docked into the ATP-binding pocket of the Human Hsp90 N-terminal domain (PDB ID: 6LTI).\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6199117/v1/218613e34a03eabf683f1a3d.png"},{"id":78336034,"identity":"b1d2744f-21e6-4dd5-8aff-5231572da8ee","added_by":"auto","created_at":"2025-03-12 07:58:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3002989,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6199117/v1/6c83c4e3-567c-4c5b-bc52-035f10bf8be8.pdf"},{"id":78334645,"identity":"c7284e5c-fa85-4587-b08e-7f35c4de3bcc","added_by":"auto","created_at":"2025-03-12 07:50:02","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":5789534,"visible":true,"origin":"","legend":"\u003cp\u003eFig S1\u003c/p\u003e","description":"","filename":"FigS1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-6199117/v1/61ebc3f1722fcea25d94c2a1.tiff"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cem\u003eIn Silico \u003c/em\u003eIdentification of Spirodioxynaphthalenes as Promising Hsp90 Inhibitors\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eNatural products represent an affluent source of myriad chemical structures with an expansive spectrum of biological activities, encompassing antimicrobial, anticancer, anti-inflammatory, and enzyme-inhibitory properties [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These naturally occurring compounds, biosynthesized by plants, microorganisms, and marine organisms, frequently exhibit complex and unique molecular architectures that engage biological targets through various mechanisms [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Moreover, numerous compounds were used as efficacious therapeutic agents to treat several pathological conditions, including cancer, infectious diseases, and cardiovascular diseases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Remarkably, natural products account for 80% of clinically approved antibiotics and 75% of anticancer drugs [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These agents operate through multifarious mechanisms, as exemplified by paclitaxel (\u003cem\u003eTaxus brevifolia\u003c/em\u003e, Pacific yew tree), which inhibits tubulin polymerization; lovastatin (fungi), which inhibits HMG-CoA reductase; and camptothecin (\u003cem\u003eCamptotheca acuminata\u003c/em\u003e, Chinese happy tree), which inhibits DNA replication [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTwo therapeutic procedures primarily drive the pharmacological treatment of cancer: small molecule-targeted therapy and conventional chemotherapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Chemotherapy employs cytotoxic agents to disrupt the cell cycle, targeting the rapid proliferation of cancer cells [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. While effective, this approach renders significant side effects (e.g., nausea, vomiting, and mucositis) and the development of multidrug resistance [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In contrast, small molecule targeted therapy (SMTT) focuses on developing chemical entities competent in selectively modulating the activity of biomolecules associated with specific oncogenic processes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Protein kinases (e.g., BCR-ABL, EGFR, CDK4/6, BRAF), proteases (e.g., the proteasome), and heat shock proteins (e.g., Hsp90) represent prominent targets in SMTT [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHsp90, a ubiquitous molecular chaperone, is upregulated by cellular stress, protein misfolding, oxidative stress, and the tumor microenvironment [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In these circumstances, Hsp90 employs the energy of ATP hydrolysis to assist in the folding and maintaining the stability of hundreds of client proteins [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Hsp90 clients, including kinases, ligases, and transcription factors, are entangled in essential cellular processes such as signal transduction, cell cycle regulation, and apoptosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Hsp90 is a dimeric protein, with each proteome comprising three structural domains. The N-terminal domain (NTD) of Hsp90 contains the ATP-binding pocket, the middle domain (MD) interacts with client proteins, and the C-terminal domain (CTD) promotes dimerization [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The high dynamicity of Hsp90 protomers allows them to experience conformational changes triggered by ATP binding and hydrolysis, which is indispensable for Hsp90 chaperone roles [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Hsp90 cochaperones stabilize Hsp90 conformations throughout the ATPase cycle and recruit client proteins to the Hsp90 chaperone machinery [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The Hsp90 chaperone cycle exhibits high selectivity, specifically targeting proteins with an intrinsic unfolding or low folding propensity to facilitate proper folding and stability [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA considerable number of the Hsp90 client proteins are related to the pathogenesis of numerous diseases, including nondegenerative diseases like Alzheimer's disease, Parkinson's disease, and many types of cancer [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Preclinical studies have indicated that breast cancer and melanoma cells depend highly on Hsp90 for stabilizing proteins such as HER2 and BRAF [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This enhanced dependency renders these neoplastic cells notably exposed to the action of Hsp90 inhibitors, which exert their therapeutic consequence by attaching to Hsp90 and disrupting the folding of these vital proteins, thereby establishing Hsp90 inhibition as a promising therapeutic strategy for treating myriad malignancies [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. According to the DrugBank database, 49 Hsp90-based inhibitors have been assessed in clinical trials for cancer treatment; however, prior to contemporary developments, none had acquired regulatory approval due to impediments in efficacy or dose-dependent toxicity profiles [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The recent regulatory approval of Pimitespib (TAS-116), the first therapeutic agent specifically targeting Hsp90-driven tumorigenesis, constitutes a substantial milestone [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Pimitespib's mechanism of action involves binding to and inhibiting both Hsp90 α and β isoforms, culminating in the degradation of oncogenic client proteins, the induction of apoptosis, and the suppression of neoplastic cell proliferation [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHsp90 inhibitors may be categorized based on their mechanism of action, with classes including N-terminal, C-terminal, or middle-domain inhibitors [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Geldanamycin (GDA), recognized as the first N-terminal Hsp90 inhibitor, was isolated from the actinomycete \u003cem\u003eStreptomyces hygroscopicus\u003c/em\u003e variety \u003cem\u003egeldanus\u003c/em\u003e [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. GDA executes its antitumor action by association with Hsp90, precluding the activation of oncogenic client proteins and thereby leading to cancer cell degradation [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Numerous GDA derivatives with enriched solubility, reduced toxicity, and enhanced anticancer properties were developed, including 17-AAG and 17-DMAG [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Likewise, the fungal natural product radicicol potently targets Hsp90's NTD, disrupting its interaction with oncogenic proteins such as Raf and Src, thus normalizing cancer cells. Despite powerful \u003cem\u003ein vitro\u003c/em\u003e antitumor activity, its poor \u003cem\u003ein vivo\u003c/em\u003e stability curbed its clinical potential [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Consequently, more stable and active analogs, including NVP-AUY922 (Luminespib), AT-13387 (onalespib), and STA-9090 (ganetespib), have been developed [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The capability of Hsp90's NTD inhibitors to orchestrate the functional consequences of the Hsp90 chaperone cycle and elicit diverse therapeutic effects makes them promising candidates for developing therapeutic interventions against both neoplastic and neurological disorders.\u003c/p\u003e \u003cp\u003eSpirodioxynaphthalenes, an expanding class of fungal secondary metabolites, are distinguished by two 1,8-dihydroxynaphthalene-derived spiroketal units merged by a spiroketal linkage [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Based on their structural characteristics, spirodioxynaphthalenes are categorized into several subclasses, including preussomerins, palmarumycins, rhytidones, rhytidenones, anteaglonialides, cladospirones, guignardins, diepoxines, ascochytatins, and decaspirones [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Spirodioxynaphthalenes are biosynthesized via polyketide pathways involving oxidative coupling or enzymatic transformations to form the spiro linkage [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The chemical structure of spirodioxynaphthalenes is characterized by two distinct features: a core structure in which a quaternary carbon atom (the spiro center) connects two naphthalene rings and the presence of various hydroxy, methoxy, and carbonyl functional groups [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The distinct structural features of these spirodioxynaphthalenes are crucial to their varied biological impacts, which span antitumor and antimicrobial activities, as well as enzymatic inhibition [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. This selective cytotoxicity, observed in multiple studies, makes them promising candidates for drug development [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTraditionally, bioactive compounds are discovered via hands-on methods like bioactivity-guided isolation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This practice involves screening a crude extract from a natural resource to specify potential bioactive compounds. Then, the crude is fractionated into small parts and analyzed to affirm the bioactivity of any determined hit [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The extensive efforts of scientists in determining and characterizing natural products have resulted in hundreds of thousands of unique entries in databases such as COCONUT, NP Atlas, and Natural Products Online (which hosts the LOTUS depository) [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Among these are hundreds of spirodioxynaphthalenes with uncharacterized biological impacts. While exploring the biological activities of natural products using classical detection methods is often constrained by financial and resource limitations, the emergence of computer-aided approaches like virtual screening and molecular docking has revolutionized drug discovery [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. These methods deliver a robust and reliable alternative, promising a bright future for recognizing targets and characterizing the potential activities of natural products.\u003c/p\u003e \u003cp\u003eThis study used \u003cem\u003ein silico\u003c/em\u003e methods to virtually screen natural product databases and identify potential inhibitors targeting the ATP binding pocket within Hsp90. Thirteen spirodioxynaphthalenes were identified from natural product databases as potential Hsp90 ATPase inhibitors. These compounds exhibit favorable drug-like properties, promising pharmacokinetic profiles, and cytotoxic potential. Their strong binding affinities, ranging from \u0026minus;\u0026thinsp;10.016 to -10.636 kcal/mol, highlight their suitability for further optimization. Analysis of their binding interactions reveals critical hydrogen bond and hydrophobic interactions with key catalytic residues, including Lys58, Gly97, and Thr184, reinforcing their potential as Hsp90 inhibitors. These findings suggest that spirodioxynaphthalenes represent a novel chemotype for developing Hsp90-targeted cancer therapeutics. Further mechanistic validation and preclinical studies are required to advance these compounds toward clinical application.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Spirodioxynaphthalenes structure preparation\u003c/h2\u003e \u003cp\u003eMK 3018, the first identified spirodioxynaphthalene, served as a model compound for \u003cem\u003ein-silico\u003c/em\u003e screening of natural product databases, including COCONUT, NP Atlas, LOTUS, and PubChem, to identify related derivatives. These databases are valuable resources for computational studies such as molecular docking and virtual screening because they provide information about the spatial arrangement of atoms in these molecules. From these databases, 222 spirodioxynaphthalene structures were selected using a Tanimoto similarity threshold of 80% compared to the model compound (see Table S1) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The SMILES representations for the selected compounds were obtained and prepared for computational analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Screening of the Hsp90 inhibitor-like compounds using docking-based virtual screening\u003c/h2\u003e \u003cp\u003eTo screen our spirodioxynaphthalene library for potential activity against Hsp90, the X-ray crystal structure of the Hsp90-NTD (PDB ID: 6LTI, resolution: 1.59 \u0026Aring;) was downloaded and prepared for molecular docking studies using AutoDock Vina 1.2.0 [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. AutoDock Vina is a widely used molecular docking software tool that provides accurate, fast, and easy-to-use prediction of small molecules' binding mode and affinity to their biological targets [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The grid defining the receptor's active site was generated using two cuboidal boxes: a larger box with dimensions 33 x 14 x 20 \u0026Aring; and a smaller box with dimensions 20 x 20 x 20 \u0026Aring; to facilitate accurate binding calculations. Docking simulations were performed using standard settings and a Lamarckian genetic algorithm, running 100 times for each ligand [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The results were analyzed from the AutoDock log files, focusing on the lowest energy of binding (LEB) to identify the most energetically favorable binding pose (conformer). The selected conformers were exported and visualized using the UCSF Chimera package to analyze the binding modes of the identified compounds with the Hsp90 protein [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Based on their docking score, 13 of the docked complexes were selected for further analysis. These complexes were ranked by binding score and interaction pose, with those exhibiting negative binding energies considered to have higher potential stability. The docking results were validated using SwissDock Attracting Cavities (AC) 2.0 [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. SwissDock's AC 2.0 is an advanced molecular docking algorithm that predicts small molecule binding to protein targets with greater flexibility, robustness, speed, and accuracy. The human Hsp90 protein structure (PDB ID: 6LTI) was similarly prepared before docking. A 20x20x20 \u0026Aring; docking grid centered at 32-13-20 \u0026Aring; was defined, and docking was performed using four Rapid Initial Conformations (RICs), high sampling exhaustivity, and a focus on buried cavities. The resulting docking data were then downloaded and visualized using UCSF Chimera.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Validation of the Binding Mode Between Spirodioxynaphthalenes and Hsp90\u003c/h2\u003e \u003cp\u003eTo gain deeper insights into the interaction between top-ranked spirodioxynaphthalene derivatives and the Hsp90 N-terminal domain (NTD), molecular docking analysis was repeated using a mutated protein. This approach allowed for identifying potential binding hot spots and evaluating the effects of specific amino acid substitutions on ligand affinity. We used PyMOL 2.1 to introduce a point mutation in residues critical for spirodioxynaphthalenes interaction [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. The mutation was performed utilizing PyMOL\u0026rsquo;s Mutagenesis Wizard, which enables precise residue modifications and structural preparation for subsequent computational analysis and molecular dynamics simulations. The modified protein structure (PDB ID: 6LTI) was then subjected to docking studies with the top-ranked molecules from the initial screening. The docking results were analyzed and visualized using UCSF Chimera, allowing for a detailed assessment of changes in binding affinity and interaction patterns resulting from the mutation. This analysis provided valuable insights into the functional significance of the key residues like Lys58 and Thr184 in ligand binding and contributed to a more comprehensive understanding of the molecular mechanisms underlying Hsp90 inhibition.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 \u003cem\u003eIn-silico\u003c/em\u003e cytotoxicity prediction in tumor cell lines\u003c/h2\u003e \u003cp\u003eCell-line cytotoxicity assays are routinely utilized in drug discovery to study potential anticancer agents and assess their safety. In this regard, computational-based examination of cytotoxicity against hundreds of tumor cell lines extensively reduces the time and expense of drug development and candidate evaluation [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. CLC-Pred 2.0 (Cell Line Cytotoxicity Predictor) is a web-based platform designed for the \u003cem\u003ein-silico\u003c/em\u003e prediction of compound cytotoxicity in non-transformed and transformed (cancer) cell lines, utilizing structural formulas as input [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. CLC-Pred employs Quantitative Structure-Activity Relationship (QSAR) models, trained using experimental cytotoxicity data from numerous cell lines, to predict activity by comparing the structural features of the input compound with those present in its database. The potential cytotoxicity of the top-ranked selected molecules against cell lines was predicted using the CLC-Pred 2.0 platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.way2drug.com/Cell-line\u003c/span\u003e\u003cspan address=\"https://www.way2drug.com/Cell-line\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) by inputting their SMILES representations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Spirodioxynaphthalenes physicochemical, pharmacokinetics, drug-likeness, and medicinal chemistry properties assessment\u003c/h2\u003e \u003cp\u003eThe thirteen top-ranked compounds were subjected to Absorption, Distribution, Metabolism, and Excretion (ADME) analysis and evaluation of their drug-likeness and medicinal chemistry properties using the Expasy SwissADME online service [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. This analysis examines several crucial physicochemical properties of the molecule. These include molecular weight; topological polar surface area (TPSA), which indicates the molecule's ability to interact with water and biological membranes; the number of rotatable bonds; the number of hydrogen bond donors and acceptors; lipophilicity (LogP), a measure of its hydrophobicity and influence on membrane permeability; and solubility (LogS). The drug-likeness properties of the molecules were evaluated using Lipinski's Rule of Five as a predictor of oral bioavailability [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Subsequent filtering using the Ghose, Veber, Egan, and Muegge criteria further refined the assessment of their suitability as drug candidates. Finally, these molecules were assessed for medicinal chemistry properties, including lead likeness (suitability for optimization) and synthetic accessibility (SA score, reflecting the ease of chemical synthesis) to determine the potential optimization of these molecules into drugs.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results and discussion","content":"\u003cp\u003eNatural products represent a significant reservoir of bioactive compounds characterized by novel chemical scaffolds [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. \u003cem\u003eIn-silico\u003c/em\u003e methodologies are increasingly recognized as robust and reliable complements to traditional in vitro techniques in discovering bioactive molecules [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The extensive repositories of compounds with uncharacterized biological activities available in current databases provide a unique opportunity for computer-aided investigations to rapidly screen for potentially active molecules, identify their biological targets, and elucidate their mechanisms of action. Computational methods were employed in this study to identify spirodioxynaphthalene derivatives as potential modulators of Hsp90 oncogenic activity. As a growing class of fungal secondary metabolites with distinctive architectures and diverse bioactivities, including antitumor and antibacterial properties, spirodioxynaphthalenes represent valuable lead compounds for medicinal chemistry.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Natural Databases screening\u003c/h2\u003e \u003cp\u003eNatural compound databases and their derivatives were screened using an 80% Tanimoto similarity threshold and Lipinski\u0026rsquo;s Rule of Five, resulting in a library of 222 compounds. This library, presented in Table S1, includes the corresponding SMILES structures and natural product database identifiers and is the foundation for further investigations in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Dockingbased virtual screening analysis\u003c/h2\u003e \u003cp\u003eDocking-based virtual screening of the 222 screened compounds (AutoDock Vina 1.2.0) revealed a range of predicted binding energies. Notably, 13 compounds displayed the most substantial binding, with LBEs ranging from \u0026minus;\u0026thinsp;10.016 to -10.636 kcal/mol (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The remaining compounds were distributed as follows: 108 compounds from \u0026minus;\u0026thinsp;9.004 to -9.972 kcal/mol, 75 compounds from \u0026minus;\u0026thinsp;8.000 to -8.995 kcal/mol, and 24 compounds from \u0026minus;\u0026thinsp;2.703 to -7.961 kcal/mol (Table S1). Sparticolin G, with an LBE of -10.636 kcal/mol, stands out among these 13 spirodioxynaphthalenes. This compound belongs to the sparticolin family (A-G), a group of biologically active oxidized spirodioxynaphthalenes isolated from the Ascomycete fungus \u003cem\u003eSparticola junci\u003c/em\u003e [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Sparticolin G has shown promising antifungal activity against various fungal species, including \u003cem\u003eSchizosaccharomyces pombe\u003c/em\u003e and \u003cem\u003eMucor hiemalis\u003c/em\u003e. While exhibiting cytotoxicity against seven mammalian cell lines, it warrants further investigation as a potential lead compound for developing novel inhibitors.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePredicted binding affinities (LBE values) and SMILES representations of spirodioxynaphthalene derivatives with high affinity for Hsp90\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSMILES\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLBE (kcal/mol)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSparticolin G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1C\u0026thinsp;=\u0026thinsp;CC(=\u0026thinsp;O)[C@@]12C3(C\u0026thinsp;=\u0026thinsp;CC(=\u0026thinsp;O)O2)OC4\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;CC5\u0026thinsp;=\u0026thinsp;C4C(=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C5)O3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.636\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1C[C@]23C4\u0026thinsp;=\u0026thinsp;C([C@H]1O)C\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C4O[C@@]5(O2)[C@H]6[C@H](O6)[C@@H](C7\u0026thinsp;=\u0026thinsp;C(C\u0026thinsp;=\u0026thinsp;CC(=\u0026thinsp;C57)O3)O)O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.417\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiepoxine Alpha\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1CC(=\u0026thinsp;O)[C@@]23[C@@]([C@H]1O)(O2)C(=\u0026thinsp;O)[C@@H]4[C@H](C35OC6\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;CC7\u0026thinsp;=\u0026thinsp;C6C(=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C7)O5)O4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.348\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGuignardin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1\u0026thinsp;=\u0026thinsp;CC2\u0026thinsp;=\u0026thinsp;C3C(=\u0026thinsp;C1)OC4([C@@H]([C@H]5[C@H](O5)C6\u0026thinsp;=\u0026thinsp;C4C\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C6O)O)OC3\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.263\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiepoxine Sigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1\u0026thinsp;=\u0026thinsp;CC2\u0026thinsp;=\u0026thinsp;C3C(=\u0026thinsp;C1)OC4([C@@H]5[C@@H](O5)C(=\u0026thinsp;O)[C@]67[C@]4(O6)C(=\u0026thinsp;O)C\u0026thinsp;=\u0026thinsp;C[C@H]7O)OC3\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.200\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnteaglonialide F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1CC(=\u0026thinsp;O)O[C@H]1[C@@H]2CC(=\u0026thinsp;O)C\u0026thinsp;=\u0026thinsp;CC23OC4\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;CC5\u0026thinsp;=\u0026thinsp;C4C(=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C5)O3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.179\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1\u0026thinsp;=\u0026thinsp;CC2\u0026thinsp;=\u0026thinsp;C3C(=\u0026thinsp;C1)O[C@@]45[C@H]6[C@H](O6)[C@@H](C7\u0026thinsp;=\u0026thinsp;C(C\u0026thinsp;=\u0026thinsp;CC(=\u0026thinsp;C74)O[C@@]3(O5)C\u0026thinsp;=\u0026thinsp;CC2\u0026thinsp;=\u0026thinsp;O)O)O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.165\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnteaglonialide E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1CC(=\u0026thinsp;O)O[C@H]1[C@@H]2CC(=\u0026thinsp;O)CCC23OC4\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;CC5\u0026thinsp;=\u0026thinsp;C4C(=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C5)O3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.141\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalmarumycin M2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1C[C@H]([C@@H]2[C@@H]([C@H]1O)C(=\u0026thinsp;O)C[C@H](C23OC4\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;CC5\u0026thinsp;=\u0026thinsp;C4C(=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C5)O3)O)O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.134\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSch53514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1\u0026thinsp;=\u0026thinsp;CC2\u0026thinsp;=\u0026thinsp;C3C(=\u0026thinsp;C1)OC4([C@H]5[C@H](O5)[C@@H]([C@@]67[C@@]4(O6)C(=\u0026thinsp;O)C\u0026thinsp;=\u0026thinsp;C[C@@H]7O)O)OC3\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.109\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1\u0026thinsp;=\u0026thinsp;CC2\u0026thinsp;=\u0026thinsp;C3C(=\u0026thinsp;C1)O[C@@]45[C@H]6[C@H](O6)C(=\u0026thinsp;O)C7\u0026thinsp;=\u0026thinsp;C(C\u0026thinsp;=\u0026thinsp;CC(=\u0026thinsp;C74)O[C@@]3(O5)C\u0026thinsp;=\u0026thinsp;C[C@@H]2O)O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.088\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalmarumycin CE2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1C[C@H]([C@@H]2[C@H]([C@H]1O)C(=\u0026thinsp;O)CCC23OC4\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;CC5\u0026thinsp;=\u0026thinsp;C4C(=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C5)O3)O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecaspirone F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1\u0026thinsp;=\u0026thinsp;CC2\u0026thinsp;=\u0026thinsp;C3C(=\u0026thinsp;C1)OC4(C\u0026thinsp;=\u0026thinsp;C[C@@H]([C@H]5[C@H]4[C@@H](C\u0026thinsp;=\u0026thinsp;C[C@@H]5O)O)O)OC3\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Detailed analysis of spirodioxynaphthalene substructures for potential Hsp90 inhibition\u003c/h2\u003e \u003cp\u003eSpirodioxynaphthalenes, diverse spirocyclic fungal metabolites, exhibit significant antitumor, antimicrobial, and enzymatic inhibition activities [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Biosynthesized through modified polyketide pathways, they encompass various structural subclasses, including preussomerins and guignardins [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].We performed molecular docking analysis to evaluate their potential as Hsp90 ATPase inhibitors, comparing their binding modes and affinities with ATP. Results demonstrated that spirodioxynaphthalenes bind to the same region of the Hsp90 NTD as ATP, exhibiting similar binding modes within the ATP-binding site (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These findings suggest spirodioxynaphthalenes compete with ATP for binding, likely acting as ATP-competitive inhibitors of Hsp90's chaperone activity. ATP interacts with Hsp90 via a combination of hydrogen bonds (Lys58, Glu47, Leu107, Phe138, Gly97, Thr152, Thr184) and hydrophobic interactions (Lys58, Leu107, Ile96, Gly97, Met98, Ala55, Asn51) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Notably, spirodioxynaphthalenes adopt a similar binding mode within the Hsp90 NTD (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), directly competing with ATP for occupancy of the catalytic pocket. This structural mimicry strongly supports their potential as ATP-competitive inhibitors, effectively targeting Hsp90 ATPase activity for therapeutic intervention. Molecular docking analysis of spirodioxynaphthalene substructures revealed a range of ligand binding energy values (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), indicating their differing binding affinities.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCalculated LBE values for spirodioxynaphthalene substructures docked to the N-terminal domain of Hsp90.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubfamily\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLBE (kcal/mol)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLBE (kcal/mol)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLBE (kcal/mol)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSparticolin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.336\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-10.636\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.429\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.763\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.971\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.334\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003ePreussomerin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.939\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.427\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYmf 1029A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.956\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.417\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eJ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-7.729\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYmf 1029B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.113\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.502\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.711\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYmf 1029C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.868\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.458\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYmf 1029D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.806\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.459\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYmf 1029E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.277\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.806\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.895\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChloropreussomerin A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-6.133\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.874\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.585\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChloropreussomerin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-5.387\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.368\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.713\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3'-O-Desmethyl-1-epipreussomerin C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.932\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"16\" rowspan=\"17\"\u003e \u003cp\u003ePalmarumycin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eB7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.074\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.565\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eB8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.489\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.703\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eB9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-7.841\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.433\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCE2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.535\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCP2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.204\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCE3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.043\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.731\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.511\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCE4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.531\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCP3a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.354\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.615\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.071\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCP4a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.786\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.844\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCP4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.972\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.577\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.323\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.907\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCP17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.824\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.379\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCP18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.333\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.631\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.477\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.713\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.657\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.558\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.719\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePalmarumycin derivative 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.242\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.569\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePalmarmycin BG-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.951\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.279\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.851\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePalmarmycin JC 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.422\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.911\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRhytidone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.992\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.986\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eRhytidenone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-2.696\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.424\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.320\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-6.784\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.688\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAnteaglonialide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.776\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-10.141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.807\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-10.179\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eCladospirone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebisepoxide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.556\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.397\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.175\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.674\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.736\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.826\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGuignardin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.284\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.613\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-7.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.657\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDiepoxine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlpha\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.348\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKappa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-7.512\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDelta\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.164\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.831\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAscochytatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003e-7.948\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eDecaspirone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.337\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-7.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.711\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.561\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-7.565\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.275\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.497\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-10.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.197\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"8\" rowspan=\"9\"\u003e \u003cp\u003eUnclassified\u003c/p\u003e \u003cp\u003eSpirodioxynaphthalenes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSCH-53823\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.658\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCID: 162959954\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCID: 156020160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.748\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSch53514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCID: 162988669\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.427\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCID: 162848350\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.768\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCJ-12,371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.416\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCID: 163065359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.745\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCID: 162914941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-8.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 10044524\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.524\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCID: 155518452\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.755\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCID: 162926480\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.593\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 162951024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.490\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCID: 155532397\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCID: 134145504\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.572\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 162957149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCID: 155555809\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.867\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCID: 134153360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.436\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 102223268\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCID: 102069972\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCID: 51354124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.443\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 102223269\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCID: 101671799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCID: 3010883\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.352\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 15224599\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCID: 101672291\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-9.425\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e3.3.1 Sparticolin subfamily\u003c/h2\u003e \u003cp\u003eTo investigate whether other members of the sparticolin family also exhibit Hsp90 affinity, we performed molecular docking simulations to assess the potential binding interactions between Hsp90 and each family member (A, B, C, D, E, and F) [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. In the analysis of the resulting docking scores, we found that sparticolin A has LBE value of -9.336 kcal/mol, sparticolin B has LBE value of -9.429 kcal/mol, sparticolin C has LBE value of -7.971 kcal/mol, sparticolin D has LBE value of -9.059 kcal/mol, sparticolin E has LBE value of -8.763 kcal/mol, Table. 2. Sparticolin F has LBE value of -9.334 kcal/mol. The observed difference in binding affinity, with sparticolin G exhibiting a 1.207 kcal/mol higher than the next closest family member (sparticolin B), is attributed to its distinct structural features. The X-ray crystallographic guided structure analysis revealed that these molecules share a common spirodioxynaphthalene core, in addition to carboxyalkylidene-cyclopentanoid (sparticolin A\u0026ndash;D), carboxyl-functionalized oxabicyclo[3.3.0]octane (sparticolin E\u0026ndash;F), and annelated 2-cyclopentenone/δ-lactone (sparticolin G) [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. The presence of a fused 2-cyclopentenone/δ-lactone motif can significantly impact a molecule's bioactivity by modulating its structural, electronic, and reactive characteristics. Docking analysis indicated that the cyclopentenone moiety of sparticolin G engages in multiple interactions with the Hsp90, including an ion-π interaction with Lys58, hydrophobic contacts with Lys58, Ala55, Asn51, Leu107, and Thr184, and a hydrogen bond with Lys58, Gly97, Thr109, Ile110, and Thr184, Table. 3, Figure. 3, and Figure. 4. The δ-lactone moiety also contributes to binding, forming a hydrogen bond with Lys58 and hydrophobic interactions with Asn51. These findings collectively further support that the fused 2-cyclopentenone/δ-lactone system significantly enhances the binding affinity of sparticolin G.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMolecular docking analysis of the top-ranked spirodioxynaphthalene derivatives binding to the Hsp90\u0026rsquo;s NTD: interaction profiles and the lowest binding energies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eInteraction Mode\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLBE (kcal/mol)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eH-bond\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eHydrophobic\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eion-π\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSparticolin G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr109, Ile110, Thr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Ala55, Asn51, Leu107, Thr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLys58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.636\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr109, Thr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Val186, Ala55, Thr184, Asn51, Leu107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.417\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly108, Thr109, Leu107, Thr184, and Gly97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVal186, Thr184, Phe138, Asn51, Leu107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.165\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Asn51, Ile91, Thr184, and Thr152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIle96, Ala55, Leu107, Phe138, Val186, Asn51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.088\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalmarumycin M2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr109, Asp102, and Thr152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIle96, Phe138, Asn51, Leu107, Thr184, and Val186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.134\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalmarumycin CE2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Asn51, Ser52, Thr109, Gly97, Thr152,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAsn51, Ile96, Phe138, Leu107, Val186, Thr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnteaglonialide E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr184, Thr109,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePhe138, Thr184, Val186, Ile96, Asn51, and Ala55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLys58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.141\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnteaglonialide F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr184, Thr109,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Gly108, Asn51, Thr184, and Leu107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLys58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.179\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGuignardin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Leu48, Asn51, Gly97, Thr184, Thr109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Asn51, Ala55, Val186,\u0026nbsp; Leu107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.263\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiepoxine Alpha\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Leu107, Ile96, Thr109, Thr184, and Thr152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAla55, Lys58, Val186,\u0026nbsp;Asn51, Gly108, Leu107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.348\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiepoxine Sigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Ile96, Thr109, Gly97, Leu107, Thr152, and Thr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAla55, Lys58, Gly108, Leu107, Val186, Asn51, Thr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.200\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecaspirone F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58,\u0026nbsp;Asn51, Glu74, Gly135, Thr184, and Thr152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Leu107,\u0026nbsp;Phe138,\u0026nbsp;Asn51, Thr184, Gly108, and\u0026nbsp;Val186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSch53514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr184, Thr109, and Thr152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Val186, Leu107, Ala55, Gly108, Asn51, Thr184, Lys58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.109\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalmarumycin B6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr184, Thr109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Thr184, Asn51, Leu107, Val186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.911\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalmarumycin C13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr184, Thr109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Asn51, Leu107, Val186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.851\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecaspirone G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr184, Thr109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Asn51, Leu107, Phe138, Met98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.711\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRhytidenone F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr184, and Thr109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Asn51, Phe138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.688\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGuignardin F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Asn51,\u0026nbsp;and Leu107, Phe138, Thr184, Asp93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.657\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCladospirone bisepoxide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr152, Thr184, Gly135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAsn51, Lys58, Leu107, Val186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.556\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAscochytatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Gly97, Thr109, Thr152, Thr184, Phe138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAsn51, Gly97, Thr184, Leu107, Thr109, Val136, Phe138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-7.948\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLys58, Glu47, Leu107, Phe138, Gly97, Thr152, Thr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLys58, Leu107, Ile96, Gly 97, Met98, Ala55, Asn51, Thr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-7.866\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e3.3.2 Preussomerins subfamily\u003c/h2\u003e \u003cp\u003ePreussomerins are spirodioxynaphthalene derivatives characterized by a core structure of two unsaturated decalin units linked by three oxygen bridges via two spiroketal carbons, one on each decalin unit [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. The preussomerin family was first recognized in 1990 with the characterization of preussomerin A from the coprophilous fungus \u003cem\u003ePreussia isomera\u003c/em\u003e [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Subsequently, approximately 20 analogs, encompassing preussomerins A\u0026ndash;L, Ymf 1029 A\u0026ndash;E, and preussomerins EG1\u0026ndash;EG4, have been isolated from diverse fungal sources, including \u003cem\u003ePreussia isomera\u003c/em\u003e, \u003cem\u003eSporormiella vexans\u003c/em\u003e, and \u003cem\u003eEdenia gomezpompae\u003c/em\u003e [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. These metabolites demonstrated various bioactivities, including antimicrobial, nematicidal, and cytotoxic, and numerous members of this family have been reported to have antitumor activity [\u003cspan additionalcitationids=\"CR49\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Chen et al. have reported that several members of this family demonstrated potent antiproliferative activity against A549, HepG2, and MCF-7 human cancer cell lines, with IC50 values ranging from 2.5\u0026ndash;9.4 micromolar [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Molecular docking analysis revealed distinct binding modes and affinities of preussomerins to Hsp90 (Table. 2). Preussomerin B exhibited a high binding affinity with a calculated ligand binding energy of -10.417 kcal/mol. At the same time, preussomerin J demonstrated a weaker interaction with Hsp90, exhibiting an LBE of -7.729 kcal/mol (Table. 2). Preussomerin B, a metabolite produced by the coprophilous fungus \u003cem\u003ePreussia isomera\u003c/em\u003e Cain, possesses a broad spectrum of biological influences [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Molecular docking analysis revealed that this bioactive compound interacts favorably with the Hsp90 ATPase domain, exhibiting a calculated binding energy of -10.417 kcal/mol. This strong binding suggests the compound's potential as a potent inhibitor of Hsp90 ATPase activity. Preussomerin B binds to Hsp90 through a combination of hydrophobic and hydrogen-bonding interactions. Its rigid bicyclic diterpene core contributes to hydrophobic interactions with Lys58, Val186, Ala55, Thr184, Asn51, and Leu107 of Hsp90. Furthermore, the hydroxy groups on the fused rings are crucial for solubility and form hydrogen bonds with Lys58, Gly97, Thr109, and Thr184 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Preussomerin D, a secondary metabolite from \u003cem\u003ePreussia cinerascens\u003c/em\u003e, shows promise as a nematicide against \u003cem\u003eBursaphelenchus xylophilus\u003c/em\u003e, as an inhibitor of coelomycetous fungi in dung, and as a potent inhibitor of Ras farnesyl-protein transferase (FPTase), suggesting potential therapeutic applications [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Molecular docking analysis revealed that this bioactive compound interacts favorably with the Hsp90 ATPase domain, exhibiting a calculated binding energy of -10.165 kcal/mol (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This strong binding suggests the compound's potential as a potent inhibitor of Hsp90 ATPase activity. The core of Preussomerin D is a spiro[4.5]decane system, which is constructed by the fusion of two rings: a cyclohexane ring and a cyclopentane ring. The cyclohexane ring is fused to a pyran ring, while the cyclopentane ring is fused to a lactone ring. This fused ring system contributes to hydrophobic interactions with Val186, Thr184, Phe138, Asn51, and Leu107 of Hsp90. Preussomerin D's spirocyclic core features diverse oxygen-containing functional groups\u0026mdash;including hydroxy, a ketone, and an ether, which contribute to its biological activity, molecule solubility, and its H-bonds interaction with Lys58, Gly108, Thr109, Leu107, Thr184, and Gly97 of Hsp90, Table.3 and Figure. S1. Preussomerin E, a secondary metabolite isolated from the fungus \u003cem\u003ePreussia isomera\u003c/em\u003e, displays a broad spectrum of biological activities. Notably, it exhibits antifungal properties and demonstrates significant cytotoxicity against various cancer cell lines, suggesting promising antitumor potential [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Molecular docking studies revealed a favorable interaction between Preussomerin E and the ATPase domain of Hsp90, with a calculated binding energy of -10.088 kcal/mol, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. This strong binding affinity suggests that Preussomerin E may act as a potent inhibitor of Hsp90 ATPase activity. Preussomerin E possesses a unique pentacyclic ring system formed by the fusion of a 1,4-dihydronaphthalene (a benzene ring fused to a cyclohexene) and a 1-tetralone (a benzene ring fused to a cyclohexanone), linked by three oxygen bridges. This architecture facilitates hydrophobic interactions with key residues of Hsp90, including Ile96, Ala55, Leu107, Phe138, Val186, and Asn51. Additionally, two hydroxy substituents contribute to hydrogen bonding with Lys58, Gly97, Asn51, Ile91, Thr184, and Thr152 of Hsp90 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Figure S1). A unique subgroup of preussomerins exists, characterized by incorporating chlorine atoms within their structure. Chloropreussomerins A and B, isolated from \u003cem\u003eLasiodiplodia theobromae\u003c/em\u003e ZJ-HQ1, exemplify this subgroup as the first reported chlorinated preussomerins [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. These compounds possess a distinctive chlorine atom at the C-8 position of their naphthalene core. Molecular docking analysis revealed that the chloride substituent in chloropreussomerins did not enhance but instead impaired binding affinity to Hsp90\u0026rsquo;s ATP-binding pocket. Specifically, Chloropreussomerin A and Chloropreussomerin B exhibited ligand binding energies (LBE) of -6.133 kcal/mol and \u0026minus;\u0026thinsp;5.387 kcal/mol, respectively\u0026mdash;values significantly weaker than those of non-chlorinated preussomerin derivatives (e.g., preussomerins B: -10.417 kcal/mol), Table.2. This suggests that the electron-withdrawing chloride group disrupts critical interactions, reducing Hsp90 inhibitory efficacy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.3.3 Anteaglonialides subfamily\u003c/h2\u003e \u003cp\u003eThe anteaglonialides family, a diverse group of spirodioxynaphthalene natural products, originates from the endophytic fungus \u003cem\u003eAnteaglonium sp. FL0768\u003c/em\u003e [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. This fungus resides within the tissues of the spikemoss \u003cem\u003eSelaginella arenicola.\u003c/em\u003e The Anteaglonialide family, incorporating members such as Anteaglonialides A-F, has exhibited various biological activities, including antibacterial, antifungal, and cytotoxic influences [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. The chemical structure of the anteaglonialides features a shared core motif, 1,8-spirodioxynaphthalene, which is linked to cyclohexane derivatives. These cyclohexane units are further connected to a γ-lactone moiety, completing the complex architecture of the molecule. This unique arrangement of rings and functional groups contributes to the structural diversity and biological activity of the anteaglonialides. Molecular docking analysis revealed that the tested compounds exhibit moderate to strong binding affinity to Hsp90 (Table. 2). Binding affinity was quantified using calculated LBE values. The following LBE values (kcal/mol) were obtained: Anteaglonialide A (-9.327), Anteaglonialide B (-9.807), Anteaglonialide C (-8.776), Anteaglonialide D (-9.102), Anteaglonialide E (-10.141), and Anteaglonialide F (-10.179). Anteaglonialide F and Anteaglonialide E demonstrated the highest binding affinity among the tested compounds, suggesting their potential as a potent Hsp90 inhibitor. Anteaglonialide E binds to Hsp90 through a combination of interactions. A hydrogen bond is formed between the ketone oxygen of its cyclohexanone ring and Lys58, Gly97, Thr184, and Thr109 of Hsp90. Additionally, the lactone ring of Anteaglonialide E participates in an ion-π interaction with Lys58, Figure. 4. Several residues, including Phe138, Thr184, Val186, Ile96, Asn51, and Ala55, contribute to hydrophobic interactions with different parts of Anteaglonialide E, Figure. 3 and Table. 3. Anteaglonialide F binds to Hsp90 through a combination of diverse interactions. A hydrogen bond is established between the ketone oxygen of its cyclohexenone ring and Lys58, Gly97, Thr184, and Thr109 of Hsp90. Furthermore, the lactone ring of Anteaglonialide F engages in an ion-π interaction with Lys58, Figure. 4. Additionally, multiple residues\u0026mdash;including Lys58, Gly108, Asn51, Thr184, and Leu107\u0026mdash;contribute to hydrophobic interactions with various regions of Anteaglonialide F, enhancing its binding stability and affinity (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.3.4 Palmarumycins subfamily\u003c/h2\u003e \u003cp\u003ePalmarumycins are about 50 members of natural products classified as spirodioxynaphthalenes [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. These secondary metabolites are synthesized by various fungi, particularly species belonging to the \u003cem\u003eDiaporthe\u003c/em\u003e and \u003cem\u003eConiothyrium\u003c/em\u003e genera [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Their distinctive structural features have attracted considerable interest owing to their unique chemical frameworks and broad spectrum of biological activities, such as antimicrobial, antifungal, antitumor, and antiviral properties [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. These structurally distinct antibiotics possess a unique architecture characterized by a 1,8-dihydroxy naphthalene unit spiro cyclically linked to a partially reduced naphthalene ring. This core scaffold is further adorned with various substituents, including hydroxy and chloride groups, significantly contributing to their structural diversity and biological activity. Molecular docking analysis revealed that the tested Palmarumycin compounds displayed moderate to strong binding affinities to Hsp90, ranging from \u0026minus;\u0026thinsp;7.841 kcal/mol for Palmarumycin B9 to -10.134 kcal/mol for Palmarumycin M2 and \u0026minus;\u0026thinsp;10.021 kcal/mol for Palmarumycin CE2 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Palmarumycin M2, a spirodioxynaphthalene compound, originates from \u003cem\u003eMicrosphaeropsis arundinis\u003c/em\u003e, a coelomycetous fungus that inhabits plants [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Palmarumycin M2 interacts with Hsp90 through hydrogen bonding and hydrophobic interactions. Three hydroxy groups on Palmarumycin M2 form hydrogen bonds with Lys58, Gly97, Thr109, Asp102, and Thr152 of Hsp90. Hydrophobic interactions involve Ile96, Phe138, Asn51, Leu107, Thr184, and Val186 of Hsp90 binding to distinct motifs on Palmarumycin M2 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Figure S1). Palmarumycin CE2, a spirodioxynaphthalene compound, is produced by \u003cem\u003eAnteaglonium\u003c/em\u003e, a fungal genus belonging to the Anteagloniaceae family within the Pleosporales order [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Palmarumycin CE2 interacts with Hsp90 through hydrogen bonds and hydrophobic interactions. Its two hydroxy groups form hydrogen bonds with Lys58, Asn51, Ser52, Thr109, Gly97, and Thr152 of Hsp90. Additionally, hydrophobic interactions are facilitated by residues Asn51, Ile96, Phe138, Leu107, Val186, and Thr184, which bind to distinct regions of Palmarumycin CE2, stabilizing the complex and enhancing its binding affinity (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Figure S1). Palmarumycin B6, a spirodioxynaphthalene compound, is synthesized by fungi of the genus \u003cem\u003eBerkleasmium\u003c/em\u003e, which belongs to the family Dematiaceae [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. These fungi are known for producing structurally unique and biologically active secondary metabolites. Palmarumycin B6, with a binding energy of -9.911 kcal/mol, exhibits two distinct modes of hydrogen bond interactions. The first is an intramolecular hydrogen bond between its adjacent hydroxy and carbonyl groups, stabilizing its internal structure. The second is an intermolecular hydrogen bond between the hydroxy group of Palmarumycin B6 and Gly97, Thr184, Thr109, and Lys58 of Hsp90, which is critical in binding to the target protein. Additionally, hydrophobic interactions are enabled by residues, Lys58, Thr184, Asn51, Leu107, and Val186, which bind to distinct regions of Palmarumycin B6, stabilizing the complex and enhancing its binding affinity to Hsp90 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Figure S1). Palmarumycin C13, a spirodioxynaphthalene compound, is produced by fungi of the genus \u003cem\u003eCladosporium\u003c/em\u003e, which encompasses some of the most prevalent indoor and outdoor molds [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Palmarumycin C13, with a binding energy of -9.851 kcal/mol, interacts with Hsp90 through hydrogen bonds and hydrophobic interactions. Specifically, its two hydroxy clusters form hydrogen bonds with Lys58, Gly97, Thr184, and Thr109 of Hsp90. Furthermore, hydrophobic interactions are mediated by residues Lys58, Asn51, Leu107, and Val186, which engage with distinct regions of Palmarumycin C13 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Figure S1). These interactions stabilize the complex and significantly enhance its binding affinity to Hsp90.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.3.5 Diepoxins subfamily\u003c/h2\u003e \u003cp\u003eDiepoxins, a unique class of spiroketal-bridged bisepoxides, have been derived from a filamentous fungus such as \u003cem\u003eBerkleasmium\u003c/em\u003e sp [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. Using NMR spectroscopy-guided structural elucidation, researchers identified these metabolites as spiro-bisnaphthalenes or epoxide-rich derivatives, distinguished by their intricate fused polycyclic frameworks [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. This discovery highlights the structural complexity and biosynthetic versatility of fungal secondary metabolites. To date, four diepoxin derivatives have been characterized within this class: diepoxin σ (sigma), diepoxin κ (kappa), diepoxin G, and diepoxin δ (delta) [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. Among these, Diepoxine Alpha\u0026mdash;a structurally related member sharing the hallmark bisepoxide and spiroketal framework of diepoxins\u0026mdash;has been deposited into the PubChem database under the identifier CID 139585239 (entry published on 2021-11-04). \u003cem\u003eIn vitro\u003c/em\u003e studies have demonstrated that these fungal-derived secondary metabolites exhibit potent cytotoxic, antifungal, and antibiotic activities, suggesting their potential as candidates for therapeutic development [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. Molecular docking analysis of these compounds revealed a spectrum of Hsp90 inhibition potential, with calculated ligand binding energies ranging from \u0026minus;\u0026thinsp;7.512 to -10.348 kcal/mol (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), correlating with moderate to potent inhibitory effects. Notably, Diepoxine Alpha (LBE = -10.348 kcal/mol) and Diepoxin σ (sigma) (LBE = -10.200 kcal/mol) exhibited the strongest binding affinities, indicative of robust Hsp90-targeting activity. In contrast, Diepoxin κ (kappa) (-7.512 kcal/mol), Diepoxin G (-8.831 kcal/mol), and Diepoxin δ (delta) (-8.164 kcal/mol) demonstrated comparatively weaker inhibition, underscoring structural variations that modulate efficacy within this compound class.\u003c/p\u003e \u003cp\u003eDiepoxin sigma, a spirodioxynaphthalene metabolite of the fungus \u003cem\u003eNeofusicoccum mangiferae\u003c/em\u003e, has been reported to possess antifungal and anticancer properties. The proposed Hsp90 inhibitory activity of Diepoxin sigma is attributed to key structural features [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. The naphthalene core is predicted to engage in hydrophobic interactions with residues Ala55, Lys58, Gly108, Leu107, Val186, Asn51, and Thr184 of Hsp90. Furthermore, the hydroxy, epoxide (two), and carbonyl (two) substituents on the dioxin ring are predicted to form hydrogen bonds with Lys58, Ile96, Thr109, Gly97, Leu107, Thr152, and Thr184 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Diepoxine Alpha binds to the ATP-binding pocket of Hsp90 via hydrogen bonding and hydrophobic interactions, driven by its spiroketal-bisepoxide structural framework. Specifically, the compound\u0026rsquo;s carbonyl group forms a hydrogen bond with Lys58, Gly97, Leu107, Ile96, Thr109, Thr184, and Thr152 of Hsp90. Concurrently, hydrophobic interactions are mediated by residues Ala55, Val186, Gly108, and Leu107, which engage with nonpolar regions of Diepoxine Alpha. Notably, Asn51 and Lys58 further stabilize the binding interface through van der Waals contacts, highlighting the synergistic role of polar and nonpolar forces in anchoring the ligand to the chaperone\u0026rsquo;s active site (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e3.3.6 Decaspirone subfamily\u003c/h2\u003e \u003cp\u003eDecaspirones are a structurally distinct subclass of spirodioxynaphthalenes, closely related to palmarumycins [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. Like their parent compounds, they retain the core spirodioxynaphthalene framework\u0026mdash;a naphthalene moiety fused to a decalin system \u003cem\u003evia\u003c/em\u003e a spiroketal bridge and two oxygen bridges. However, Decaspirones are characterized by a critical divergence: they incorporate a trans-decalin moiety, in contrast to the cis-decalin stereochemistry feature of palmarumycins. This stereochemical inversion at the decalin ring junction represents the hallmark structural distinction between the two subfamilies, influencing their conformational dynamics and bioactivity [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. To date, nine decaspirones (A\u0026ndash;I) have been isolated from diverse fungal sources, reflecting distinct ecological niches [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Decaspirones A\u0026ndash;E were derived from the freshwater aquatic fungus \u003cem\u003eDecaisnella thyridioides\u003c/em\u003e, while Decaspirones F\u0026ndash;I were sourced from the saprophytic fungus \u003cem\u003eHelicoma viridis\u003c/em\u003e [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. Molecular docking analysis of Decaspirones targeting the Hsp90 ATPase domain revealed significant variability in ligand binding energies, highlighting structure-dependent inhibition (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Decaspirone F exhibited the strongest binding affinity (LBE = -10.016 kcal/mol), followed by Decaspirone G (-9.711 kcal/mol). In comparison, Decaspirone D showed markedly weaker interaction (-7.008 kcal/mol). This gradient in binding efficacy underscores the critical influence of decalin stereochemistry and spiroketal substituents on Hsp90 engagement, positioning Decaspirone F as a lead candidate for therapeutic development. A synergistic interplay of hydrogen bonding and hydrophobic interactions within the ATP-binding pocket drives Decaspirone F\u0026rsquo;s strong binding affinity to Hsp90. The compound\u0026rsquo;s hydroxy groups form critical hydrogen bonds with residues Lys58, Asn51, Glu74, Gly135, Thr184, and Thr152, while its hydrophobic regions engage residues Leu107, Phe138, Thr184, Gly108, and Val186 through van der Waals contacts. Notably, Asn51 and Lys58 participate in both interaction types, stabilizing the ligand\u0026rsquo;s orientation (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This dual binding mechanism, anchored to conserved regions of Hsp90\u0026rsquo;s catalytic domain, underscores Decaspirone F\u0026rsquo;s structural complementarity and potent inhibitory potential. Decaspirone G exhibited a moderately strong binding affinity to Hsp90\u0026rsquo;s ATP-binding pocket (LBE = -9.711 kcal/mol), driven by a synergistic interplay of hydrogen bonding and hydrophobic interactions. Lys58, Gly97, Thr184, and Thr109 of Hsp90 are engaged with hydrogen bonds with polar parts of Decaspirone G. Hydrophobic contacts with Lys58, Asn51, Leu107, Phe138, and Met98 further anchored the ligand to conserved regions of the catalytic domain (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Figure S1). This cooperative binding mechanism compensates for its slightly weaker affinity than Decaspirone F (LBE = -10.016 kcal/mol), underscoring the structural adaptability of spirodioxynaphthalenes in targeting Hsp90\u0026rsquo;s functional epitopes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e3.3.7 Rhytidone and Rhytidenone subfamily\u003c/h2\u003e \u003cp\u003eRhytidone and Rhytidenone are structurally related subgroups within the spirodioxynaphthalene family, distinguished by their decalin-derived modifications and distinct fungal origins [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Both compounds share a core spirodioxynaphthalene framework, where a naphthalene moiety is fused to a decalin system via a spiroketal bridge stabilized by oxygen linkages. The key divergence lies in their decalin substituents: Rhytidone features a cis-decalin moiety bearing a carbonyl group (e.g., ketone). Rhytidenone incorporates a trans-decalin moiety with a carbonyl group and at least one alkene, enhancing conformational rigidity and bioactivity. To date, three spirodioxynaphthalene (Rhytidone A\u0026ndash;C) and eight rhytidenones (A\u0026ndash;H) have been characterized. Rhytidenones have been evaluated for their anticancer potential, with Rhytidenone F emerging as the most potent cytotoxic agent [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Other derivatives, such as Rhytidenones B\u0026ndash;E, exhibit broad-spectrum antimicrobial properties, including antifungal and antibacterial activities [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. In parallel, Rhytidone A was assessed for cytotoxicity against human Ramos cells using the Cell Titer-Glo assay after 24-hour exposure [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. While initial testing revealed a reduction in cell viability, the activity outcomes remain inconclusive.\u003c/p\u003e \u003cp\u003eMolecular docking analysis revealed that Rhytidenone subclasses engage Hsp90 with varying binding affinities. Rhytidenone F exhibited the strongest binding mode (LBE = -9.688 kcal/mol), whereas Rhytidenones A and H bound poorly (LBE = -2.696 and \u0026minus;\u0026thinsp;6.784 kcal/mol, respectively; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Rhytidenones B, C, D, E, and G showed moderate binding affinity (LBE values of -9.283, -9.410, -9.424, -9.456, and \u0026minus;\u0026thinsp;9.320 kcal/mol, respectively), Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Within the ATP binding pocket of Hsp90, Rhytidenone F interacts with Lys58, Gly97, Thr184, and Thr109 via hydrogen bonds, and with Lys58, Asn51, and Phe138 through hydrophobic contacts (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Figure S1).\u003c/p\u003e \u003cp\u003eOn the other side, the Rhytidone series (A\u0026ndash;C), with moderate binding affinities (-9.023 to -8.986 kcal/mol), underperforms compared to most Rhytidenones (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This disparity may stem from structural distinctions, such as the absence of alkene groups or reliance on \u003cem\u003ecis\u003c/em\u003e-decalin configurations, which reduce conformational rigidity and limit hydrophobic engagement.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e3.3.8 Guignardin subfamily\u003c/h2\u003e \u003cp\u003eGuignardins are a family of bioactive spirodioxynaphthalenes, complex polycyclic secondary metabolites primarily isolated from endophytic fungi, especially \u003cem\u003eGuignardia\u003c/em\u003e species [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Their defining structural feature is a spirobisnaphthalene core, formed by two naphthalene units linked via a spiroketal bridge stabilized by two oxygen atoms. Individual guignardins (A-F) are distinguished by their substituents and stereochemistry variations. The primary source of guignardins is the endophytic fungus \u003cem\u003eGuignardia\u003c/em\u003e sp. KcF8 is isolated from plants such as \u003cem\u003eDioscorea zingiberensis\u003c/em\u003e [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. These compounds have also been found in fungi associated with mangroves and terrestrial environments. Guignardins possess promising pharmacological properties, including enzymatic inhibition, antifungal activity, and cytotoxicity [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Consequently, they are being investigated for potential therapeutic applications in diabetes, cancer, and inflammation based on their ability to modulate enzyme activity. Molecular docking analysis demonstrated that guignardins bind to the ATP-binding pocket of Hsp90 with distinct interaction profiles and varying affinities. Among these, Guignardin B (LBE = -10.263 kcal/mol) and Guignardin F (LBE = -9.657 kcal/mol) exhibited the most potent binding, driven by complementary interactions with conserved residues in the catalytic domain (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Guignardin B forms hydrogen bonds with Lys58, Leu48, Asn51, Gly97, Thr184, and Thr109 of Hsp90, while hydrophobic contacts with Lys58, Asn51, Ala55, Val186, and Leu107 stabilize its positioning (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Notably, Lys58 and Asn51 participate in polar and nonpolar interactions, underscoring their dual role in ligand anchoring. Guignardin F engages with Lys58, Gly97, and Thr184 of Hsp90 via hydrogen bonds interaction and relies on hydrophobic interactions with Lys58, Asn51, and Leu107, Phe138, Thr184, and Asp93 to secure its binding (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Figure S1). The robust affinities of Guignardin B and F highlight their potential to competitively inhibit ATP hydrolysis, disrupting Hsp90's chaperone function and offering a pathway for cancer therapy. Guignardin D (LBE = -7.033 kcal/mol) exhibits weak binding affinity to Hsp90, likely due to steric and electronic incompatibilities arising from its structural features. The acetal moiety introduces steric bulk, disrupting optimal positioning within the ATP-binding pocket. At the same time, the carboxylic acid group may destabilize hydrophobic interactions or induce unfavorable electrostatic repulsion with adjacent residues (e.g., Lys58 or Thr184). This dual interference underscores functional group optimization's importance in enhancing binding efficacy in future analogs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section3\"\u003e \u003ch2\u003e3.3.9 Cladospirone subfamily\u003c/h2\u003e \u003cp\u003eCladospirones represent a structurally distinct subgroup within the spirobisnaphthalene family, closely related to palmarumycins [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. While retaining the core spirobisnaphthalene framework\u0026mdash;comprising a naphthalene moiety fused to a decalin system via a spiroketal bridge and dual oxygen bridges\u0026mdash;Cladospirones are defined by a critical structural divergence: the presence of a β-hydroxy group at the C-8a position, contrasting sharply with the cis-decalin stereochemistry characteristic of palmarumycins. This stereochemical inversion at the decalin ring junction is the hallmark distinction between the two subfamilies, profoundly influencing their conformational flexibility, molecular interactions, and bioactivity profiles. To date, nine Cladospirone derivatives have been identified within the spirobisnaphthalene family. The inaugural member, Cladospirone bisepoxide (Cladospirone A), was first isolated in 1994 from the fungus \u003cem\u003eSphaeropsidales\u003c/em\u003e sp., distinguished by its spiroketal-bridged bisepoxide framework [\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. Subsequent research in 2000 expanded this family with the discovery of Cladospirones B\u0026ndash;I from \u003cem\u003eSphaeropsidales\u003c/em\u003e sp. F-24\u0026prime;707 under optimized fermentation conditions [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]. These derivatives showcase remarkable structural diversity, driven by hydroxylation patterns, stereochemical permutations, and oxygen bridge modifications, underscoring the biosynthetic versatility of their fungal producers. Cladospirones, due to their unique structural properties, exhibit a range of bioactivities, including antimicrobial, anticancer, and enzyme modulation effects. Molecular docking studies indicate moderate binding affinities of these compounds toward the Hsp90 ATPase binding pocket (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Cladospirone bisepoxide (-9.556 kcal/mol) and Cladospirone D (-9.397 kcal/mol) exhibited the most potent binding affinities within this group, likely due to their spirobisnaphthalene structural motifs. Cladospirone bisepoxide forms multiple hydrogen bonds with key Hsp90 residues, including Lys58, Gly97, Thr152, Thr184, and Gly135. Hydrophobic interactions with Asn51, Lys58, Leu107, and Val186 further contribute to its stability within the binding pocket (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Figure S1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003e3.3.10 Ascochytatin subfamily\u003c/h2\u003e \u003cp\u003eAscochytatin is a bioactive spirodioxynaphthalene metabolite isolated from the marine-derived fungus \u003cem\u003eAscochyta\u003c/em\u003e sp. NGB4. First identified in 2008, this compound features a spirobisnaphthalene scaffold\u0026mdash;a structural hallmark of its class\u0026mdash;comprising fused naphthalene moieties interconnected via a spiroketal bridge [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. Distinctively, Ascochytatin\u0026rsquo;s core structure is further substituted with an epoxy ring and three hydroxy groups, enhancing its bioactivity. These functional groups contribute to its antimicrobial potential, enzyme modulation effects, and cytotoxic properties, positioning it as a promising candidate for therapeutic development. Molecular docking simulations of Ascochytatin, the sole characterized member of its family, revealed a moderate binding affinity (LBE = -7.948 kcal/mol) against Hsp90. The interaction is stabilized by a synergistic interplay of H-bonds with catalytic residues (e.g., Lys58, Gly97, Thr109, Thr152, Thr184, and Phe138), hydrophobic contacts within the ATP-binding pocket (e.g., Asn51, Gly97, Thr184, Leu107, Thr109, Val136, Phe138 ), and ion-π interactions involving aromatic moieties and Lys58 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Figure S1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section3\"\u003e \u003ch2\u003e3.3.11 Miscellaneous spirodioxynaphthalenes\u003c/h2\u003e \u003cp\u003eIn addition to the subfamilies of spirodioxynaphthalenes, a group of compounds that did not belong to the previously mentioned categories was identified within natural product databases (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These compounds, which feature a spirodioxynaphthalene structure, underwent molecular docking analysis to evaluate their potential activity in modulating Hsp90. Based on their docking score these compounds have shown weak to strong binding potential against Hsp90 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Sch53514 (LBE = -10.109 kcal/mol) and compound CID: 156020160 (-9.748 kcal/mol) show the strongest binding affinity, making them the most promising candidates for Hsp90 inhibition. These spirodioxynaphthalenes likely have highly favorable interactions with the Hsp90 active site, driven by hydrogen bonding and hydrophobic contacts. The Sch53514 chemical structure analysis revealed that this molecule is like the cladospirone subfamily. This is evident by its shared structural features, including a naphthalene moiety fused to a decalin system through a spiroketal bridge, two oxygen bridges, and a β-hydroxy group at the C-8a position. The compound with CID 156020160 is a spirobisnaphthalene derivative with structural features of a tricyclic tridecane core with a spirocyclic connection to a cyclohexene ring. The molecule also incorporates oxygen-containing functional groups: a carbonyl at position 1, a hydroxy group at position 6', and a methoxy group at position 3'. Both molecules interact with Hsp90 through a combination of hydrophobic and H-bond interactions. Sch53514 interacts with Lys58, Gly97, Thr184, Thr109, and Thr152 of Hsp90 through hydrogen bonds, while Lys58, Val186, Leu107, Ala55, Gly108, Asn51, Thr184, Lys58 of Hsp90 engage in hydrophobic interactions with various motifs of Sch53514 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Mode of binding verification\u003c/h2\u003e \u003cp\u003eLys58, Gly97, and Thr184 frequently interact with spirodioxynaphthalene derivatives and the Hsp90 NTD (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Lys58 is the most frequently involved residue in H-bonding, appearing in all 20 cases (100%). This highlights its critical role in stabilizing ligand binding. Gly97 and Thr184 also significantly contribute to hydrogen bonding, appearing in 80% and 75% of cases, suggesting that these residues are key mediators of ligand-protein interactions. Thr109 and Asn51 further support ligand binding through hydrogen bonds but with lower frequency, appearing in 65% and 30% of cases. Hydrophobic interactions play a crucial role in stabilizing the binding of ligands within the ATP-binding pocket. Key residues Thr184, Leu107, and Lys58 are each involved in 65% of observed hydrophobic interactions, highlighting their significant contribution to nonpolar binding. Asn51 (60%) and Val186 (40%) also play notable roles, further stabilizing the ligand within the pocket. Additional residues, including Ile96, Ala55, and Phe138, contribute to hydrophobic stabilization with a lower frequency of 30% each. These findings suggest a network of hydrophobic contacts working in concert to secure the ligand within the Hsp90 protein. Ion-π interactions appear to play a negligible role, with Lys58 showing three occurrences with 100% overall contribution. The obtained data suggests that targeted mutagenesis of Lys58, Thr184, or Gly97 could significantly impact ligand binding, making them key residues for experimental validation in drug discovery efforts. To further investigate the roles of these residues, we performed molecular docking studies using Hsp90 NTD mutants. Specifically, we generated Lys58Ala, Thr184Ala, Gly97Ala, Lys58/Thr184Ala, and Lys58/Gly97/Thr184Ala mutants (PDB ID: 6LTT) using PyMOL 2.1. This approach allowed us to assess the impact of these mutations on ligand binding.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFrequency and Percentage of Key Hsp90 NTD Residues Involved in Spirodioxynaphthalene Derivative Binding Across Different Interaction Types\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmino Acid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eH-Bond\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eHydrophobic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eIon-π\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCount\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePercentage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCount\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePercentage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCount\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePercentage\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLys58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1000%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGly97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThr184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThr109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsn51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeu107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThr152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIle96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAla55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhe138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVal186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGly108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGly135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSer52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlu74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsp102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeu48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsp93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMet98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVal136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAnalysis of docking results revealed that mutations generally reduced the binding affinity of spirodioxynaphthalene derivatives to Hsp90 NTD (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The extent to which binding affinity is affected differs across compounds and depending on the specific mutation(s). The Lys58 to Ala mutation significantly reduced binding affinity for several compounds, highlighting the importance of Lys58 in ligand binding. Notable reductions include Decaspirone F (-1.905 kcal/mol), Palmarumycin M2 (-1.257 kcal/mol), Palmarumycin CE2 (-0.802 kcal/mol), and Preussomerin D (-0.635 kcal/mol). These findings support the established role of Lys58 in hydrophobic, hydrogen bond, and ion-pi interactions with ligands. However, Preussomerin E exhibited a slight \u003cem\u003eincrease\u003c/em\u003e in binding affinity (0.059 kcal/mol) upon mutation, suggesting that the introduced mutation may induce a conformational change that enhances binding for this specific ligand. Thr184 to Ala mutation had a variable effect, sometimes slightly increasing binding (e.g., Preussomerin E), the combined Lys58 \u0026amp; Thr184 to Ala mutation predictably resulted in the largest decrease in binding affinity. The Gly97 to Ala mutation had a diverse influence on the binding affinity of spirodioxynaphthalene derivatives to Hsp90 NTD. A subset of compounds (Decaspirone F, Preussomerin B, Preussomerin D, Palmarumycin M2, Palmarumycin CE2, and Diepoxine Sigma) exhibited a reduction in binding affinity upon mutation, with Decaspirone F showing the most significant decrease (-1.536 kcal/mol). Conversely, another group of compounds (Sparticolin G, Preussomerin E, Anteaglonialide E, Anteaglonialide F, Guignardin B, Diepoxine Alpha, and Sch53514) showed a slight increase in binding affinity. These contrasting effects indicate that the mutation does not uniformly impact all ligands, suggesting that spirodioxynaphthalene derivatives interact with the Hsp90 NTD through distinct binding mechanisms. The impact of multiple points mutations on the binding affinity of spirodioxynaphthalene derivatives to Hsp90 NTD was investigated. Both the double mutation (Lys58 and Thr184 to Ala) and the triple mutation (Lys58, Gly97, and Thr184 to Ala) consistently reduced binding affinity across all tested compounds, underscoring the crucial role of these residues in stabilizing protein-ligand interactions. The most prominent reductions in binding affinity were observed for Decaspirone F (-1.723 kcal/mol for the double mutation and \u0026minus;\u0026thinsp;1.726 kcal/mol for the triple mutation), Palmarumycin M2 (-1.433 kcal/mol and \u0026minus;\u0026thinsp;1.412 kcal/mol, respectively), and Palmarumycin CE2 (-1.03 kcal/mol and \u0026minus;\u0026thinsp;1.018 kcal/mol, respectively). The consistent and substantial decrease in binding affinity with the triple mutation suggests that Lys58, Gly97, and Thr184 act synergistically to create a critical interaction hotspot (e.g., hydrophobic and hydrogen bond interactions) that are essential for stabilizing the binding of these derivatives to Hsp90 NTD.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eImpact of \u003cem\u003ein-silico\u003c/em\u003e mutations on the binding affinity of spirodioxynaphthalene derivatives to Hsp90\u0026rsquo;NTD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWT Hsp90\u0026rsquo; NTD LBE (kcal/mol)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c7\" namest=\"c3\"\u003e \u003cp\u003eMutated Hsp90\u0026rsquo;s NTD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eLys58\u0026rarr;Ala\u003c/b\u003e (kcal/mol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eGly97\u0026rarr;Ala\u003c/b\u003e (kcal/mol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eThr184\u0026rarr;Ala\u003c/b\u003e (kcal/mol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eLys58 \u0026amp; Thr184\u0026rarr;Ala\u003c/b\u003e (kcal/mol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eLys58, Gly97, \u0026amp; Thr184\u0026rarr;Ala\u003c/b\u003e (kcal/mol)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSparticolin G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.636\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.217\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-10.741\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.431\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.909\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.918\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.417\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-9.870\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-10.060\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.738\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.591\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.605\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.165\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-9.530\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-9.986\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.712\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.285\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.344\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.088\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-10.147\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-10.095\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.760\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.928\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.936\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalmarumycin M2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.134\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-8.877\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-9.440\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.230\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-8.701\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-8.722\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalmarumycin CE2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-9.219\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-9.472\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.176\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-8.991\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnteaglonialide E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.141\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-9.724\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-10.145\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.902\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.453\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.473\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnteaglonialide F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.179\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-9.667\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-10.218\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.917\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.368\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.390\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGuignardin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.263\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-9.967\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-10.274\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.960\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.557\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.546\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiepoxine Alpha\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.348\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-9.928\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-10.354\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-10.039\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.629\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.618\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiepoxine Sigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.200\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-9.980\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-9.813\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.651\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.509\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.751\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecaspirone F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-8.111\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-8.480\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-8.304\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-8.284\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-8.290\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSch53514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-10.109\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-9.549\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-10.129\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-9.806\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-9.262\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-9.272\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Spirodioxynaphthalenes physicochemical, pharmacokinetics, drug-likeness, and medicinal chemistry properties assessment\u003c/h2\u003e \u003cp\u003eThe physicochemical properties of the top-ranked spirodioxynaphthalenes derivatives were evaluated to assess their drug-likeness and potential for therapeutic applications (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). These molecules have a molecular weight (MW) range of 320.3\u0026ndash;368.34 g/mol. All compounds fall within the optimal range for drug-like molecules (typically\u0026thinsp;\u0026lt;\u0026thinsp;500 Da), which agrees with Lipinski RO5 and indicates good potential for cell permeability and oral bioavailability. The spirodioxynaphthalene molecules demonstrate limited rotatable bonds (0\u0026ndash;1), indicating a rigid conformation crucial for binding specificity to Hsp90. The number of hydrogen bond acceptors ranges from 5 to 7, while hydrogen bond donors range from 0 to 3. These values are acceptable for drug-like molecules, suggesting favorable interactions with the Hsp90's NTD. Topological Polar Surface Area (TPSA) quantifies the polar surface area of a molecule, calculated as the sum of surface areas contributed by oxygen, nitrogen, and their attached hydrogen atoms. Optimal TPSA values are context-dependent, influenced by factors such as the molecule's target site, administration route, and therapeutic class. For instance, anticancer agents often exhibit acceptable TPSA values between 70\u0026ndash;120 \u0026Aring;\u0026sup2;, while orally available drugs typically fall within 60\u0026ndash;100 \u0026Aring;\u0026sup2;. The top-ranked spirodioxynaphthalenes showed TPSA values ranging from 61.83\u0026ndash;101.05 \u0026Aring;\u0026sup2;, suggesting favorable drug-like properties, particularly for oral administration, and demonstrating good potential as anticancer agents. ESOL (Estimated Solubility) is a computational model that predicts the aqueous solubility of a compound based on its molecular properties. ESOL provides two key values: ESOL Log S, which reflects solubility in mol/L (higher Log S values indicate more excellent solubility), and ESOL solubility (mg/mL), representing the estimated concentration in water. Regarding Log S, compounds with values \u0026gt; -2.0 are considered highly soluble, moderately soluble between \u0026minus;\u0026thinsp;2.0 and \u0026minus;\u0026thinsp;4.0, and those \u0026lt; -4.0 are poorly soluble. The top-ranked spirodioxynaphthalenes derivatives have ESOL Log S) ranging from \u0026minus;\u0026thinsp;4.09 (for Sparticolin G) to -2.67 ( for Sch53514), suggesting soluble to mode moderately soluble molecules.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eIn-silico\u003c/em\u003e prediction of the physicochemical properties of the top-ranked spirodioxynaphthalenes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecule\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFormula\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMW (g/mol)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e#RB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e#HBA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e#HBD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTPSA (\u0026Aring;\u0026sup2;)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eESOL Log S\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eESOL Solubility (mg/ml)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eESOL Class\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSparticolin G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e320.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e61.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-4.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.62E-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eModerately soluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePreussomerin B\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e16\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e368.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e100.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-2.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.96E-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSoluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePreussomerin D\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e364.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e97.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-2.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4.02E-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSoluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePreussomerin E\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e364.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e97.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-3.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.19E-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSoluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePalmarumycin M2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eO\u003csub\u003e6\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e356.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e96.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.69E-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSoluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePalmarumycin CE2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e340.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e75.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-3.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.71E-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSoluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnteaglonialide E\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e338.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e61.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-4.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.14E-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eModerately soluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnteaglonialide F\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e16\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e336.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e61.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-4.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.17E-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eModerately soluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGuignardin B\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e14\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e334.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e71.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-4.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.90E-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eModerately soluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiepoxine Alpha\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e14\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e366.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e97.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-2.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4.21E-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSoluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiepoxine Sigma\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e364.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e97.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-2.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4.31E-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSoluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDecaspirone F\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e338.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e79.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-3.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.31E-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSoluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSch53514\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e14\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e366.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e101.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-2.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.85E-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSoluble\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe spirodioxynaphthalene derivatives exhibited favorable drug-likeness properties, as determined by Lipinski's Rule of Five, Ghose, Veber, Egan, and Muegge filters, bioavailability score, lead-likeness violations, and synthetic accessibility (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). All spirodioxynaphthalene derivatives analyzed comply with Lipinski's Rule of Five, indicating favorable absorption and permeability profiles. Additionally, consistent with the favorable physicochemical properties observed in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, all spirodioxynaphthalene derivatives meet the Ghose, Veber, Egan, and Muegge criteria, solidifying their potential as drug-like candidates. Based on computational predictions, all molecules have a Bioavailability Score of 0.55, suggesting a 55% probability of successful oral absorption in humans. Most spirodioxynaphthalene derivatives demonstrate 0 or 1 lead-likeness violation, signifying desirable characteristics for lead compounds in drug discovery. Compounds with a single violation (Preussomerin B/D/E, Palmarumycin M2, Diepoxine Alpha/Sigma, Sch53514) might require minor structural adjustments for improved lead-likeness. Finally, the Synthetic Accessibility (SA) Score, a computational metric for estimating the ease of chemical synthesis, ranges from 1 (very easy) to 10 (very difficult). The SA scores for these molecules fall between 4.24 and 5.78, suggesting a moderate level of synthetic complexity suitable for drug development. Collectively, Sparticolin G, Anteaglonialide E/F, and Guignardin B stand out as the most promising candidates due to their excellent drug-likeness profiles, including zero lead-likeness violations, good bioavailability, and more straightforward synthesis. Although Sch53514, Preussomerin B, and Diepoxine Sigma may require more complex synthetic routes, they remain viable candidates with favorable drug-like properties. All compounds warrant further optimization and preclinical studies.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eIn-silico\u003c/em\u003e prediction of the drug-likeness of the top-ranked spirodioxynaphthalenes based on Lipinski, Veber, Ghose, Egan rules, and Muegge filters, bioavailability score, lead-likeness violations, and synthetic accessibility.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecule\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLipinski #violations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGhose #violations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVeber #violations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEgan #violations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMuegge #violations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBioavailability Score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLead likeness #violations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSynthetic Accessibility\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSparticolin G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePreussomerin B\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePreussomerin D\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePreussomerin E\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePalmarumycin M2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePalmarumycin CE2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnteaglonialide E\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnteaglonialide F\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGuignardin B\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiepoxine Alpha\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiepoxine Sigma\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDecaspirone F\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSch53514\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Cytotoxicity Prediction\u003c/h2\u003e \u003cp\u003eCLC-Pred (Cell Line Cytotoxicity Predictor), a web-based platform, predicts compound cytotoxicity in normal and cancerous cell lines using structural formulas as input. This \u003cem\u003ein-silico\u003c/em\u003e approach employs QSAR models trained on experimental cytotoxicity data [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. We used CLC-Pred 2.0 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.way2drug.com/Cell-line\u003c/span\u003e\u003cspan address=\"https://www.way2drug.com/Cell-line\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) with SMILES representations to predict the potential anticancer activity of the selected top-ranked spirodioxynaphthalenes (Table\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). The \u003cem\u003ein-silico\u003c/em\u003e analysis using CLC-Pred reveals potential anticancer activity for several spirodioxynaphthalene derivatives. Guignardin B, Diepoxine Alpha, Diepoxine Sigma, and Sch53514 stand out with exceptionally high predicted probabilities of activity (Pa values approaching 1.0) against both MDA-MB-231 (breast adenocarcinoma) and MCF 7.00 (breast carcinoma) cell lines, indicating potent potential cytotoxicity. Preussomerin D and E also exhibit high predicted activity, particularly in MCF 7.00 cells. Guignardin B demonstrates a broader potential, showing activity against breast cancer and renal carcinoma (RXF 393). Several compounds exhibit varied activity across cell lines, suggesting potential cell-type selectivity. For instance, Palmarumycin M2 shows moderate predicted activity against melanoma (M19-MEL) and pancreatic cancer (CFPAC-1). Decaspirone F and Anteaglonialide F show modest predicted activity against brain (Hs 683) and colon (DLD-1) cancers, respectively. Anteaglonialide E exhibits the lowest predicted activity against colon cancer. Palmarumycin CE2 and Anteaglonialide F show lower predicted efficacy in breast cancer than other tested compounds.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab8\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCLC-Pred Cytotoxicity Predictions for Spirodioxynaphthalenes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePa\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePi\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCell-line\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCell-line name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTissue/organ\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSparticolin G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.870\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.841\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreussomerin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.798\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePreussomerin D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.914\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.718\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePreussomerin E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.942\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.773\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ePalmarumycin M2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.748\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM19-MEL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSkin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.753\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.679\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCFPAC-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePancreatic carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePancreas\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalmarumycin CE2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.698\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnteaglonialide E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.565\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLD-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eColon adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eColon\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAnteaglonialide F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.696\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.608\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eGuignardin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.914\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.906\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.833\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRXF 393\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRenal carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eKidney\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.688\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePC-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSmall cell lung carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.637\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-468\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDiepoxine Alpha\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.995\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.993\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDiepoxine Sigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.993\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.993\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eDecaspirone F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.831\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.779\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.681\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHs 683\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOligodendroglioma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBrain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSch53514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.996\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB-231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.995\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMCF\u0026nbsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBreast carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e* Pa: Probability of Activity ** Pi: Probability of Inactivity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Conclusion and future direction","content":"\u003cp\u003eHsp90 is a critical molecular chaperone accountable for appropriately folding and functioning considerable client proteins implicated in life-threatening diseases, including cancer. Consequently, targeting Hsp90 activity offers a promising therapeutic strategy. Spirodioxynaphthalenes are expanding fungal secondary metabolites with largely unexplored biological activities. This report aims to specify spirodioxynaphthalene-derivatives as potential inhibitors of Hsp90 activity. Using integrated computer-aided drug discovery pipelines, we identified thirteen spirodioxynaphthalenes from natural product databases promising inhibitors against Hsp90 activity as an initial step in novel drug development. All these compounds exhibit favorable drug-like properties, promising pharmacokinetic profiles, and cytotoxic potential. Their strong binding affinities, ranging from \u0026minus;\u0026thinsp;10.016 to -10.636 kcal/mol, highlight their potential for further optimization. Detailed interaction analysis demonstrates critical hydrogen bonding and hydrophobic interactions with key catalytic residues, including Lys58, Gly97, and Thr184, reinforcing their role as Hsp90 inhibitors. These findings recommend that these natural products represent a novel chemotype for developing Hsp90-targeted cancer therapeutics. Further mechanistic studies and preclinical proof are necessary to facilitate their transition into clinical applications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNewman DJ, Cragg GM (2020) Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. J Nat Prod 83:770\u0026ndash;803\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChaachouay N, Zidane L (2024) Plant-Derived Natural Products: A Source for Drug Discovery and Development. Drugs Drug Candidates 3:184\u0026ndash;207\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsma ST, Acaroz U, Imre K et al (2022) Natural Products/Bioactive Compounds as a Source of Anticancer Drugs. 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J Antibiot (Tokyo) 61:142\u0026ndash;148\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Al-Ahliyya Amman University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Bioactive small molecules, Cancer, Hsp90, Molecular docking, Spirodioxynaphthalenes","lastPublishedDoi":"10.21203/rs.3.rs-6199117/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6199117/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe ATPase activity of Hsp90 is critical for cancer progression, as it maintains the stability of oncogenic proteins, thereby supporting tumor cell survival. Although small-molecule inhibitors targeting this activity have shown preclinical promise, toxicity and insufficient efficacy have hindered their progress in clinical trials. Accordingly, expanding the search for novel Hsp90 inhibitors remains paramount. Spirodioxynaphthalenes, a rapidly expanding class of fungal secondary metabolites, exhibit a remarkable breadth of bioactive properties, including antitumor, antibacterial, antifungal, and enzymatic inhibitory activities. This study employed an \u003cem\u003ein-silico\u003c/em\u003e methodology to identify spirodioxynaphthalene derivatives as potential inhibitors of Hsp90\u0026rsquo;s ATPase activity. We identified thirteen spirodioxynaphthalenes from natural product databases as potential inhibitors of Hsp90 ATPase activity. These compounds, with their favorable drug-like properties, promising predicted pharmacokinetics and cytotoxicity, and potent binding energies ranging from \u0026minus;\u0026thinsp;10.016 to -10.636 kcal/mol, emerge as compelling candidates for further optimization. Their binding interactions, which reveal key hydrogen bonds and hydrophobic interactions with catalytic residues Lys58, Gly97, and Thr184, bolster their potential as Hsp90 inhibitors. These findings firmly suggest that spirodioxynaphthalenes could represent a novel chemotype for developing Hsp90-targeted cancer therapeutics, providing a ray of hope for the future of cancer treatment. Further mechanistic validation and preclinical development are necessary to advance these compounds towards clinical application.\u003c/p\u003e","manuscriptTitle":"In Silico Identification of Spirodioxynaphthalenes as Promising Hsp90 Inhibitors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-12 07:41:51","doi":"10.21203/rs.3.rs-6199117/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ff659624-5087-4063-9e36-2ed113dd4079","owner":[],"postedDate":"March 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-12T07:41:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-12 07:41:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6199117","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6199117","identity":"rs-6199117","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}