Discovery of tricin as a novel ADAMTS1 inhibitor via molecular docking and ADMET predictions for inhibiting cancer metastasis

Discovery of tricin as a novel ADAMTS1 inhibitor via molecular docking and ADMET predictions for inhibiting cancer metastasis | 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 Discovery of tricin as a novel ADAMTS1 inhibitor via molecular docking and ADMET predictions for inhibiting cancer metastasis Sharma Ayushi, Chien-Huang Liao, Yung‑Wei Lin, Yu-Ching Wen, Gupta Shankar, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7521823/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 Background: ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) plays a crucial role in extracellular matrix (ECM) remodeling, cancer metastasis, and regulation of the tumor microenvironment. As ADAMTS1 has been implicated in tumor-promoting mechanisms across various cancer types, its inhibition has shown potential as a therapeutic strategy for aggressive cancers. Methods: In this study, we employed molecular docking and pharmacokinetic profiling to identify potential small-molecule inhibitors of ADAMTS1. In total, 26 natural and synthetic compounds were screened against ADAMTS1 using AutoDock Vina, followed by absorption, distribution, metabolism, excretion, and toxicity (ADMET)predictions via SwissADME. The in vitro migratory ability of cancer cells was assessed by transwell migration assay. Protein-based biochemical assays such as Western blotting to investigate ADAMTS1-regulated pathway. Results: We identified tricin as the lead compound (binding energy: –10.93 kcal/mol), a natural product with high oral absorption and non-carcinogenic properties. Functional assays revealed that tricin, at non-toxic concentrations, significantly inhibited the migratory and adhesive abilities of various oral squamous cell carcinoma (OSCC) and clear cell renal cell carcinoma (ccRCC) cell lines by suppressing expression or activation of ADAMTS1 and its downstream effectors including epidermal growth factor receptor (EGFR), Src, and focal adhesion kinase (FAK). Conclusions : These findings provide a computational framework for identifying tricin as a potential ADAMTS1 inhibitor and support its validation as a therapeutic agent for treating cancer metastasis, particularly in cancer types with high ADAMTS1 expression. ADAMTS1 Molecular docking Tricin Metastasis Renal cell carcinoma Oral squamous cell carcinoma Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the ADAMTS family—a group of secreted enzymes that play important roles in remodeling the extracellular matrix (ECM) and regulating cellular interactions with the matrix [ 1 ]. These enzymes contribute to various physiological processes, including tissue homeostasis, wound healing, and the pathogenesis of several diseases, including inflammatory disorders, cardiovascular diseases, and cancers [ 1 – 4 ]. ADAMTS1, in particular, was shown to exert tumor-promoting functions, positioning it as a key player in the complex biology of cancer [ 2 , 5 , 6 ]. During tumorigenesis, the expression and activity of ADAMTS1 are often altered, leading to significant changes in the tumor microenvironment (TME) [ 7 , 8 ]. In various types of cancers, including renal cell carcinoma (RCC), oral squamous cell carcinoma (OSCC), and breast and other cancers, ADAMTS1 expression was linked to tumor progression, metastasis, and a poor prognosis [ 9 – 11 ]. The multifaceted role of ADAMTS1 in cancer is attributed to its ability to interact with various substrates, including ECM components such as versican (VCAN) and matrix metalloproteinases (MMPs), and its involvement in signaling pathways critical for tumor growth and spread [ 2 ]. For example, ADAMTS1 was shown to regulate anoikis, a type of programmed cell death that occurs when cells detach from the ECM. In RCC, ADAMTS1 contributes to anoikis resistance by activating key signaling pathways, such as the VCAN-epidermal growth factor receptor (EGFR) axis [ 10 ], and this axis reinforces ADAMTS1 expression through positive feedback. This resistance is a critical factor that enables cancer cells to survive while in circulation, thereby facilitating metastasis [ 12 ]. Moreover, ADAMTS1 plays a critical role in promoting the epithelial-to-mesenchymal transition (EMT), a process that endows cancer cells with enhanced migratory and invasive capabilities [ 2 ]. In OSCC, ADAMTS1 was shown to regulate the ADAMTS1-L1 cell adhesion molecule (L1CAM)-EGFR signaling axis, thereby facilitating the EMT and contributing to lymph node metastasis [ 9 ]. In non-small cell lung cancer (NSCLC), ADAMTS1 was reported to induce an EMT pathway via regulating transforming growth factor (TGF)-β [ 6 ]. In metastatic prostate cancer, expressions of ADAMTS1 and EMT-related markers, such as zinc finger E-box-binding homeobox 1 (ZEB1) and snail family transcription repressor 1 (SNAI1), were significantly associated with a poor prognosis [ 13 ]. Moreover, ADAMTS1 was reported to affect the invasive phenotype of glioma stem cells by regulating the Notch1-SRY box 2 (SOX2) signaling pathway [ 14 ]. These findings further highlight the role of ADAMTS1 in driving cancer cell metastasis, particularly in aggressive tumor types. Given the critical role of ADAMTS1 in cancer progression—regulating key processes such as cell stemness, adhesion, invasion, metastasis, and ECM remodeling—its inhibition represents a promising strategy for anticancer therapy. For instance, Hirano et al. demonstrated that antibody-mediated blockade of ADAMTS1 effectively suppressed breast cancer growth in a mouse model [ 15 ]. Some peptide-based inhibitors against ADAMTS1 were reported [ 16 ]. However, specific small-molecule inhibitors targeting ADAMTS1 are not yet available. In this study, we employed molecular docking and pharmacokinetic analyses to identify potential small-molecule inhibitors of ADAMTS1. In total, 30 compounds including isoflavonoids, flavones, alkaloids, and rare or less-studied phytochemicals were sourced from traditional Chinese medicinal herbs. These natural and synthetic compounds were subjected to virtual screening using ADMET profiling and AutoDock Vina. Promising hit compounds identified through an in silico analysis were subsequently evaluated through functional assays to confirm their inhibitory potential against ADAMTS1. Materials and methods Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions using SwissADME Initially, SMILES (Simplified Molecular Input Line Entry System) representations of 30 compounds were retrieved from PubChem ( https://pubchem.ncbi.nlm.nih.gov ). These compounds were then analyzed using SwissADME ( http://www.swissadme.ch/ ) to evaluate their pharmacokinetic (PK) and pharmacodynamic properties, including ADMET. Assessing these parameters is essential for understanding the drug-likeness and therapeutic potential of the compounds [ 17 ]. This analysis used various parameters, including physicochemical properties, lipophilicity, water solubility, PKs, drug-likeness, and medicinal chemistry aspects. Physicochemical descriptors such as molecular weight (MW), molecular refractivity (MR), the count of specific atom types, and polar surface area (PSA) were assessed. The PSA was calculated using the topological PSA (TPSA) method, which considers sulfur and phosphorus as polar atoms. This descriptor helps estimate ADMET properties, particularly related to absorption and blood-brain barrier (BBB) penetration. Another important descriptor is the partition coefficient, used to calculate lipophilicity, which is essential for predicting the PKs of a molecule. Water solubility is also a key factor, especially for drugs intended for oral administration, as solubility greatly influences absorption. For parenteral administration, high solubility in water is necessary to ensure that an adequate dose can be delivered in a small volume. The PK section includes predictions for passive human intestinal absorption (HIA) and BBB permeability, as well as identification of compounds as substrates or non-substrates of P-glycoprotein (Pgp). It also evaluates potential interactions with cytochrome P450 (CYP) enzymes, which are important for assessing drug-drug interactions and risks of toxicity due to reduced drug clearance or metabolite accumulation. The drug-likeness of compounds was assessed using multiple rules: Lipinski, Ghose, Veber, Egan, and Muegge. These filters were developed by pharmaceutical companies to evaluate the structural and physicochemical suitability of compounds as oral drug candidates. Compounds violating any of these rules were flagged. Additionally, the Abbott Bioavailability Score was used to estimate the probability of a compound achieving at least 10% oral bioavailability, based on factors such as the total charge and TPSA. This comprehensive screening helped identify compounds with favorable PK profiles. To ensure the overall safety, stability, and drug development potential of the selected compounds, further evaluations were conducted using the Medicinal Chemistry section of the SwissADME platform. Compounds were screened for structural risks using two filters: PAINS (Pan-Assay Interference Compounds), which identifies substructures that may cause false-positive biological results, and Brenk alerts, which detect potentially toxic or unstable fragments. Additionally, compounds were evaluated for lead-likeness to determine their suitability for further chemical optimization, focusing on appropriate size and lipophilicity. Together, these evaluations helped prioritize the most promising compounds for further experimental validation. Compounds that showed no Lipinski violations were subjected to a molecular docking analysis to analyze binding of the shrink database. Preparation of protein and ligands The crystal structure of ADAMTS1 was prepared for molecular docking studies using MGL Tools vers. 1.5.6 ( https://ccsb.scripps.edu/mgltools/downloads/ ). Protein preparation involved several key steps to ensure its stability and suitability for a docking analysis. Initially, during protein preparation, only those water molecules located within 3 Å of the co-crystallized ligand were retained, as they may play a critical role in stabilizing ligand interactions through hydrogen bonding or bridging effects. All other water molecules were removed to reduce noise and improve the accuracy of the docking results. Subsequently, polar hydrogen atoms were added to the protein structure to account for hydrogen bonding interactions, and partial Kollman charges were assigned to optimize the electrostatic environment of the active site. Further, the protein was converted into PDBQT format required for AutoDock-based docking studies [ 18 ]. Following protein preparation, grid generation was performed to define the docking region. The grid box was centered on the active site of ADAMTS, corresponding to the binding site of the reference inhibitor quantitative functional group (QFG). The grid box was set with dimensions of 24 × 24 × 24 Å along the x-, y-, and z-axes, respectively, with a spacing of 1 Å, providing a comprehensive search space for ligand binding during the docking process. The Grid box was generated on supplied coordinates of x = 10.15, y=-12.98, and z = 10.31. Ligand molecules were initially designed and sketched using ChemDraw software. These two-dimensional (2D) structures were then imported into Chem3D for three-dimensional (3D) conversion and geometric optimization. Energy minimization of the ligands was carried out using the MMFF94 (Merck Molecular Force Field) force field, with an root mean square (RMS) gradient convergence criterion set to 0.001 to ensure a stable and low-energy conformation. After minimization, ligand structures were saved in protein data bank (PDB) format and further processed in MGL Tools 1.5.6 for docking, including the addition of Gasteiger charges, identification of torsional bonds, and conversion into the PDBQT format required for AutoDock-based docking studies. Molecular docking Molecular docking was carried out using AutoDock Vina [ 18 – 20 ] to study how the selected ligands bound to the target protein, ADAMTS1 (PDB ID: 3Q2G). The docking focused on the active site of the protein to ensure that the ligands interacted with the important region responsible for its function. In this process, the protein structure was kept fixed, while the ligands were allowed to move and change shape to fit into the binding site. For each ligand, nine possible binding positions were generated, and their binding strengths were measured. Results were ranked based on the binding energy, where lower values showed stronger and more-stable interactions. To check the accuracy of the results, the compounds were docked again, and the RMS deviation (RMSD) was calculated. Docking results were also viewed to see how the ligands and protein interacted. This helped in choosing the most suitable compounds for further testing, including studies on their safety and effectiveness. Visualization of binding interactions To further analyze molecular interactions between ADAMTS1 and docked ligands, Discovery Studio Visualizer ( https://www.3ds.com/products/biovia ) [ 21 ] was used to identify hydrogen bonds, hydrophobic interactions, van der Waals forces, and π–π stacking interactions. These interactions are critical for evaluating the stability and specificity of ligand binding. In addition, PyMOL ( https://www.pymol.org/ ) [ 21 ] was employed for 3D visualization of the docked complexes, allowing for detailed examination of each ligand’s orientation within ADAMTS1’s active site. This visualization provides valuable insights into how the structural features of the ligands influence their binding affinity and conformational stability. Understanding these interactions is essential for selecting lead compounds with strong potential for further biological validation and drug development. Compounds that showed hits and proper binding interactions with ADAMTS1 were used for further analysis. Materials Tricin (HY-N1127) was obtained from MedChemExpress (Monmouth Junction, NJ, USA). Fetal bovine serum (FBS), antibiotics, molecular weight (MW) markers, trypsin-EDTA, and other medium supplements were sourced from Life Technologies (Gaithersburg, MD, USA). The pLEX-MCS-ADAMTS1 expression construct was kindly provided by Dr. T.C. Kuo (National Taiwan University, Taipei, Taiwan). Antibodies against ADAMTS1 (AF5867) and GAPDH (60004-1-Ig) were respectively purchased from R&D Systems (Minneapolis, MN, USA) and Proteintech Group (Chicago, IL, USA). Antibodies against epidermal growth factor receptor (EGFR; #4267), phosphorylated (p)-focal adhesion kinase (FAK; #3281), and p-Src (#2101) were obtained from Cell Signaling Technology (Danvers, MA, USA). Cell lines and cell culture Human OSCC cell lines—SAS, HSC-3, HSC-3M, and SCC9—were obtained from the Japanese Collection of Research Bioresources (JCRB) Cell Bank (Osaka, Japan), while the RCC cell lines—Caki-1, 786-O, and A498—were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA). SAS and SCC9 cells were cultured in Dulbecco’s modified Eagle medium/Nutrient Mixture F-12 (DMEM/F-12; Gibco, Grand Island, NY, USA), whereas HSC-3, HSC-3M, Caki-1, and A498 cells were maintained in minimum essential medium (MEM; Gibco). 786-O cells were cultured in RPMI-1640 medium. All media were supplemented with 10% fetal bovine serum (FBS) and 100 U/mL penicillin-streptomycin. Cells were incubated at 37°C in a humidified atmosphere containing 5% CO 2 . Western blot assay Total cell lysates were prepared and quantified as previously described [ 22 ]. Proteins (30–50 µg) were resolved by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidene difluoride (PVDF) membranes (Merck Millipore, Burlington, MA, USA). Membranes were probed with primary and horseradish peroxidase (HRP)-conjugated secondary antibodies, then visualized using an enhanced chemiluminescence (ECL) reagent (TOOLS, New Taipei City, Taiwan). Chemiluminescence was detected with the MultiGel-21 imaging system (TOP BIO, New Taipei City, Taiwan). Cell viability assay After treating OSCC and ccRCC cells with various concentrations of tricin for either 24 or 72 h, 5000 cells were seeded into individual wells of a 96-well plate. Cell viability was assessed by adding 100 µl of medium containing 10% Cell Counting Kit-8 (CCK-8; cat. no. 96992; MilliporeSigma, Rockville, MD, USA) to each well. The assay was conducted at 37°C, and the absorbance at 450 nm was measured hourly for up to 4 h. Transwell migration assay The in vitro migratory ability of cancer cells was assessed as previously described [ 23 ]. Briefly, (5–8) × 10 4 OSCC or RCC cells were seeded into the upper chamber of a transwell insert (24-well; 8-µm pore size; Corning Costar, Corning, NY, USA) containing serum-free medium, with or without candidate compounds at the indicated concentrations. The lower chamber was filled with medium supplemented with 10% FBS as a chemoattractant. After 24 h incubation at 37°C in a 5% CO 2 atmosphere, cells on the upper side of the membrane were removed, and the membrane was fixed in 100% methanol for 10 min. Migrated cells on the lower surface were stained with 1% crystal violet (Sigma-Aldrich, St. Louis, MO, USA) and counted under a light microscope (100× magnification, three random fields per well). Establishment of ADAMTS1 overexpression of indicated cancer cells The pLEX-MCS-ADAMTS1 expression construct was generously provided by Dr. T.C. Kuo (National Taiwan University, Taipei, Taiwan). To achieve ADAMTS1 overexpression, lentiviral particles carrying the pLEX-MCS-ADAMTS1 construct were produced and used to infect cells for 24 h, following a protocol described in our previous study [ 24 ]. Wound-healing assay Caki-1 cells with manipulated ADAMTS1 expression (2 × 10⁵ cells/well) were seeded in 24-well plates and cultured for 24 h. A wound was then created by scratching the cell monolayer with a pipette tip. Cells were subsequently incubated in complete medium for another 24 h, and wound edges were photographed using a phase-contrast microscope at 100× magnification. Data collection from bioinformatics analyses RNA sequencing data for ccRCC (KIRC; n = 535) and HNSCC (HNSC; n = 519) were obtained from The Cancer Genome Atlas (TCGA) dataset via the UCSC Xena platform. A focal adhesion signature score was calculated using a single-sample gene set enrichment analysis (ssGSEA). The gene set for the focal adhesion pathway was derived from the Gene Ontology (GO) database. A Spearman correlation analysis was performed to assess the relationship between the focal adhesion signature and ADAMTS1 gene expression. Cell-adhesion assay ADAMTS1 was either stably knocked down in RCC and OSCC cells, or cells were treated with various concentrations of tricin for 24 h. Cells were then resuspended at a density of 2 × 10⁵ cells/mL in serum-containing medium and seeded into six-well plates. After a 1.5-h incubation period, nonadherent cells were removed by two rounds of gentle phosphate-buffered saline (PBS) washing. Adherent cells were subsequently fixed and stained with either 0.4% crystal violet or sulforhodamine (Sigma-Aldrich) for 15 min. After extensive rinsing, the dye was extracted using 30% acetic acid or 10 mM Tris base, and the absorbance was measured at 590 or 570 nm on a microplate reader (SpectraMax M2; Molecular Devices, Sunnyvale, CA, USA). Statistical analysis Data are presented as the mean ± standard deviation (SD). Statistical analyses were conducted using SPSS vers. 20 (SPSS, Chicago, IL, USA), and quantitative data were processed with GraphPad Prism 7 (GraphPad Software, San Diego, CA, USA). Differences between two groups were assessed using a two-tailed Student’s t -test. Results Binding affinity analysis Molecular docking analysis of 26 compounds revealed tricin, dichotomitin, belamcandin, wogonin, and feralolide as the top five ligands with the most robust interactions with the active site of ADAMTS1 (Table 1 ). Among them, tricin showed the highest binding affinity with a score of − 10.93 kcal/mol. It formed hydrogen bonds with SER183 and GLU150, a π-interaction with HIS149, and metal coordination with ZN401. Dichotomitin exhibited the second strongest binding (− 8.235 kcal/mol), interacting with HIS176 and GLU150, forming a π-interaction with HIS149, and coordinating with ZN401. Belamcandin and wogonin respectively showed similar binding energies of − 8.159 and − 8.131 kcal/mol. Belamcandin formed hydrogen bonds with PHE145 and THR146, while wogonin interacted with GLU150. Feralolide, with a binding energy of − 8.04 kcal/mol, formed bonds with HIS176 and GLU150 and coordinated with ZN401 (Table 2 ). Table 1 Binding affinities of ligands from the molecular docking analysis Sl. no. Ligands Binding affinity (kcal/mol) 1 Belamcandin -8.159 2 Daidzein -6.682 3 Dehydrotanshinone II A -5.411 4 Dichotomitin -8.235 5 Dihydrosanguinarine -6.311 6 Duartin -8.009 7 Feralolide -8.04 8 Flemiphilippinin C -7.859 9 Formononetin -7.76 10 Glycyrol -5.492 11 Licochalcone a -7.274 12 Lupiwighteone -7.92 13 Lyoniresinol -5.727 14 Matsukaze lactone -5.379 15 Menisporphine -6.927 16 Mucronulatol -7.983 17 Noririsflorentin -7.462 18 Norwogonin -7.938 19 Phaseolin -5.56 20 Phaseollidin -5.573 21 Rhamnazin -7.844 22 Rhamnocitrin -7.137 23 Schisandrin -3.382 24 Tricin -10.93 25 Vestitone -7.033 26 Wogonin -8.131 Bold font indicates the top five ligands with the strongest interactions at the ADAMTS1 active site. Table 2 Top 5 ligands with binding affinities and amino acid interactions Compound Name Amino Acid residues Distance (°) Type of Intreaction Docking Score (kcal/mol) QFG THR114 3.41872 Conventional Hydrogen Bond -8.677 LEU118 2.86962 Conventional Hydrogen Bond SER180 3.5477 Carbon Hydrogen Bond GLY119 3.58187 Carbon Hydrogen Bond ZN401 2.23124 Metal-Acceptor ZN401 2.14407 Metal-Acceptor ASP116 3.38927 Halogen (Fluorine) GLN113 3.81507 Pi-Donor Hydrogen Bond LEU182 3.88554 Pi-Sigma ALA179 3.58141 Alkyl LEU185 4.32508 Alkyl PHE145 4.6581 Pi-Alkyl PHE274 4.32333 Pi-Alkyl LEU185 5.20093 Pi-Alkyl Tricin ZN401 2.02765 Attractive Charge -10.93 SER183 2.11342 Conventional Hydrogen Bond GLU150 1.8912 Conventional Hydrogen Bond SER183 1.97624 Conventional Hydrogen Bond THR146 2.42323 Carbon Hydrogen Bond HIS159 2.76302 Carbon Hydrogen Bond HIS176 2.53743 Carbon Hydrogen Bond HIS149 3.83175 Pi-Pi Stacked HIS149 3.5382 Pi-Pi Stacked ALA179 3.3913 Alkyl LEU185 4.35449 Alkyl PHE145 4.07508 Pi-Alkyl PHE274 5.18681 Pi-Alkyl LEU182 5.23801 Pi-Alkyl ALA179 4.69816 Pi-Alkyl LEU182 5.16305 Pi-Alkyl Dichotomitin GLU150 2.52109 Conventional Hydrogen Bond -8.235 HIS176 2.80349 Conventional Hydrogen Bond THR146 3.72301 Carbon Hydrogen Bond GLN142 3.33478 Carbon Hydrogen Bond SER183 3.47781 Carbon Hydrogen Bond ZN401 3.56856 Pi-Cation HIS149 3.85191 Pi-Pi Stacked HIS149 3.86144 Pi-Pi Stacked LEU182 5.08461 Alkyl PHE145 5.30532 Pi-Alkyl HIS149 4.78871 Pi-Alkyl PHE274 4.44197 Pi-Alkyl LEU182 5.23368 Pi-Alkyl LEU182 5.08041 Pi-Alkyl Belamcandin THR146 3.09688 Conventional Hydrogen Bond -8.159 PRO275 3.74199 Carbon Hydrogen Bond SER183 3.71 Carbon Hydrogen Bond GLU150 3.77129 Carbon Hydrogen Bond SER183 3.42795 Carbon Hydrogen Bond LEU182 3.44176 Pi-Sigma HIS149 4.77412 Pi-Pi Stacked PHE145 4.79578 Pi-Pi T-shaped LEU118 4.87969 Alkyl PRO275 5.10733 Alkyl PRO275 3.93077 Alkyl PHE145 4.9264 Pi-Alkyl HIS149 4.0166 Pi-Alkyl HIS149 4.47592 Pi-Alkyl HIS187 4.66042 Pi-Alkyl PHE274 4.95244 Pi-Alkyl LEU182 4.72414 Pi-Alkyl LEU185 4.50287 Pi-Alkyl Wogonin GLY119 2.93215 Conventional Hydrogen Bond -8.131 GLU150 2.65143 Conventional Hydrogen Bond THR146 3.45227 Carbon Hydrogen Bond MET181 3.68867 Carbon Hydrogen Bond ZN401 4.95048 Pi-Cation LEU182 3.82946 Pi-Sigma HIS149 3.94882 Pi-Pi Stacked MET181 4.18898 Alkyl LEU182 3.92455 Alkyl LEU118 5.28565 Pi-Alkyl LEU182 5.43079 Pi-Alkyl ALA179 5.0156 Pi-Alkyl Feralolide ZN401 2.04044 Attractive Charge -8.04 GLY119 2.97439 Conventional Hydrogen Bond GLU150 2.62508 Conventional Hydrogen Bond HIS176 3.19744 Conventional Hydrogen Bond LEU182 3.60918 Pi-Sigma ALA179 5.08992 Pi-Alkyl QFG, quantitative functional group. For docking validation, we checked key amino acids required for protein inhibition and compared them with interactions of the co-crystallized ligand, QFG. The 2D and 3D interaction diagrams for the top five ligands, compared with QFG, are shown in Fig. 1 . Comparative analysis of amino acid residues shows that QFG interacts with a unique and partially overlapping set of residues when compared with other candidate compounds. QFG notably binds with THR114, LEU118, SER180, GLY119, ASP116, GLN113, LEU182, ALA179, LEU185, PHE145, and PHE274, indicating a diverse range of interactions. Among these, LEU182, LEU185, ALA179, PHE145, and PHE274 are shared with multiple other candidates such as tricin, dichotomitin, belamcandin, and wogonin, suggesting these residues may represent key binding sites. The residue ZN401 appears frequently across QFG, tricin, wogonin, and feralolide, pointing to a common metal-binding interaction. However, QFG also exhibits unique contacts such as THR114, SER180, ASP116, and GLN113, which are not observed in the other compounds, potentially contributing to a distinct binding mode. In contrast, other candidates like tricin and belamcandin show extensive interactions with HIS149 and SER183, which are absent in QFG, indicating differences in their binding preferences (Fig. 1 A-L and Table 2 ). We further superposed all docked ligands with QFGs. This helped visualize the alignment and assess how closely the new ligands mimicked the original binding mode (Fig. 1 M). These results indicated strong and stable protein-ligand interactions, with tricin emerging as the most promising candidate. Molecular properties of selected ligands Further, all candidate ligands were evaluated for their drug-likeness, key physicochemical parameters including MW, hydrogen bond donors and acceptors, Log P, TPSA, and Lipinski’s rule violations. The MWs of compounds ranged from 254.242 g/mol (daidzein) to 624.551 g/mol (isorhamnetin-3-O-β-D-rutinoside). Based on the highest binding affinity, tricin met the essential drug-likeness criteria. It has a molecular weight of 330.293 g/mol, which falls well within the acceptable range for oral drugs, and it possesses only five rotatable bonds, indicating good molecular rigidity. Tricin also has two hydrogen bond donors and 5.25 hydrogen bond acceptors, suggesting a good balance for forming specific interactions without compromising permeability. The log P value of 1.919 reflects moderate lipophilicity, which supports both membrane permeability and aqueous solubility. Its TPSA is 114.167 Å 2 , which is within the acceptable range for oral bioavailability. Importantly, tricin did not violate any of Lipinski’s rules, further confirming its suitability as a drug-like molecule (Table 3 ). Table 3 Evaluation of drug-likeness of molecules based on Lipinski’s rule of five Sr. no. Molecule Rotatable bonds Molecular weight H-bond donors H-bond acceptors Log P TPSA (Å2) Violation 1 Amurensin_qt 14 534.516 7 13.75 0.005 213.36 3 2 Belamcandin 6 358.347 0 5.25 3.438 83.431 0 3 Daidzein 3 254.242 2 4 1.814 80.486 0 4 Dehydrotanshinone II A 0 292.334 0 4.5 2.807 61.443 0 5 Dichotomitin 5 358.304 1 6 2.273 109.332 0 6 Dihydrosanguinarine 0 333.343 0 4 3.615 40.483 0 7 Duartin 5 332.352 2 4.5 3.252 69.078 0 8 E-6-O-p-methoxycinnamoyl scandoside meth 15 564.542 5 18.35 -0.248 204.967 2 9 Feralolide 7 344.32 2 6 1.356 145.898 0 10 Flemiphilippinin C 6 434.488 1 4.5 5.452 87.042 1 11 Formononetin 3 268.268 1 4 2.644 66.244 0 12 Glycyrol 5 366.37 2 5.25 3.037 96.795 0 13 Isoquercetin (2) 11 464.382 7 13.75 -1.463 219.83 2 14 Isorhamnetin-3-o-beta-d-rutinoside 15 624.551 8 20.55 -1.867 258.173 3 15 Licochalcone a 9 338.402 2 4.25 3.91 74.376 0 16 Lupiwighteone 6 338.359 2 3.75 3.416 95.192 0 17 Lyoniresinol 10 420.458 4 7.9 2.32 113.209 0 18 Matsukaze lactone 3 350.327 0 6.5 2.457 94.587 0 19 Menisporphine 3 321.332 0 5.25 3.023 57.788 0 20 Mucronulatol 4 302.326 2 3.75 2.998 66.789 0 21 Noririsflorentin 5 372.331 0 6 2.774 95.637 0 22 Norwogonin 3 270.241 2 3.75 1.763 97.582 0 23 Phaseolin 1 322.36 1 3 4.227 46.252 0 24 Phaseollidin 4 324.376 2 3 3.98 59.962 0 25 Rhamnazin 5 330.293 2 5.25 2.051 114.286 0 26 Rhamnocitrin 4 300.267 2 4.5 1.914 106.873 0 27 Schisandrin 7 432.513 1 5.25 5.186 57.062 1 28 Tricin 5 330.293 2 5.25 1.919 114.167 0 29 Vestitone 3 286.284 2 5 1.932 85.794 0 30 Wogonin 3 284.268 1 3.75 2.451 83.191 0 TPSA, topological polar surface area. PK property predictions using SwissADME As shown in Table 4 , the water solubility, PKs, and drug-likeness profiles of five compounds—tricin, dichotomitin, belamcandin, wogonin, and feralolide—were analyzed. Solubility data, predicted using ESOL (estimated solubility) and Ali models, classified most of the compounds as moderately soluble, with minor variations. Tricin exhibited an ESOL solubility of 0.0252 mg/ml and 0.00306 mg/ml in the Ali model, while dichotomitin showed slightly higher solubilities of 0.0305 (ESOL) and 0.00723 mg/ml (Ali). Belamcandin and wogonin maintained moderate solubilities across both models, although belamcandin was classified as poorly soluble in the Silicos-IT model. Feralolide displayed the lowest solubility in the Ali model (0.00114 mg/ml) but was deemed soluble by Silicos-IT. Table 4 Pharmacokinetic properties of the top five ligands Molecule Water solubility ESOL Log S ESOL solubility (mg/ml) ESOL solubility (mol/l) ESOL class Ali Log S Ali solubility (mg/ml) Ali solubility (mol/l) Ali class Silicos-IT class Tricin -4.12 2.52E-02 7.63E-05 Moderately soluble -5.03 3.06E-03 9.26E-06 Moderately soluble Moderately soluble Dichotomitin -4.07 3.05E-02 8.51E-05 Moderately soluble -4.7 7.23E-03 2.02E-05 Moderately soluble Moderately soluble Belamcandin -4.24 2.06E-02 5.74E-05 Moderately soluble -4.77 6.10E-03 1.70E-05 Moderately soluble Poorly soluble Wogonin -4.23 1.66E-02 5.85E-05 Moderately soluble -4.85 4.01E-03 1.41E-05 Moderately soluble Moderately soluble Feralolide -4.15 2.45E-02 7.11E-05 Moderately soluble -5.48 1.14E-03 3.30E-06 Moderately soluble Soluble Molecule Pharmacokinetics Human intestinal absorption BBB permeant Pgp substrate CYP1A2 inhibitor CYP2C19 inhibitor CYP2C9 inhibitor CYP2D6 inhibitor CYP3A4 inhibitor log Kp (cm/s) Tricin High No No Yes No Yes Yes Yes -6.14 Dichotomitin High No No Yes No Yes Yes Yes -6.51 Belamcandin High No No Yes No Yes Yes Yes -6.17 Wogonin High No No Yes No Yes Yes Yes -5.56 Feralolide High No No No No No No No -6.13 Molecule Drug likeness Medicinal chemistry Lipinski #violations Ghose #violations Veber #violations Egan #violations Muegge #violations Bioavailability score PAINS #alerts Brenk #alerts Lead likeness #violations Tricin 0 0 0 0 0 0.55 0 0 0 Dichotomitin 0 0 0 0 0 0.55 0 0 1 Belamcandin 0 0 0 0 0 0.55 0 0 1 Wogonin 0 0 0 0 0 0.55 0 0 0 Feralolide 0 0 0 0 0 0.55 0 0 0 ESOL, estimated solubility; PAINS, Pan-Assay Interference Compounds; BBB, blood-brain barrier; Pgp, P-glycoprotein. PK profiling revealed high GI absorption for all compounds, but none was capable of penetrating the BBB or acting as a Pgp substrate. With the exception of feralolide, which showed no inhibitory action on cytochrome P450 enzymes, the remaining four compounds consistently inhibited CYP1A2, CYP2C9, CYP2D6, and CYP3A4. Skin permeability (log Kp) values ranged from − 6.51 to -5.56, indicating low dermal absorption. The drug-likeness evaluation confirmed compliance with the Lipinski, Ghose, Veber, Egan, and Muegge rules for all compounds, with no violations detected. The bioavailability score was uniform (0.55) for all five, indicating moderate bioavailability. There were no PAINS or Brenk alerts, suggesting a low risk of promiscuous reactivity. However, dichotomitin and belamcandin had a single lead-likeness violation each, highlighting potential challenges in optimization for lead development. Collectively, these results established a clear understanding of the physicochemical, PKs, and drug-likeness characteristics of the studied compounds. Among the five compounds analyzed, tricin demonstrated the most favorable overall profile based on water solubility, PKs, and drug-likeness characteristics. In terms of solubility, while tricin was classified as moderately soluble by both the ESOL and Ali models (0.0252 and 0.00306 mg/ml, respectively), it maintained a consistent moderate solubility rating across all three predictive models (ESOL, Ali, and Silicos-IT), avoiding the poor solubility classification seen for belamcandin. Despite being a non-BBB permeant and non-Pgp substrate, its balanced enzyme inhibition profile suggested a promising pharmacological spectrum. Furthermore, tricin excelled in the drug-likeness and medicinal chemistry evaluations with zero violations of the Lipinski, Ghose, Veber, Egan, and Muegge criteria, indicating strong compliance with drug-like properties. It also maintained a moderate bioavailability score of 0.55, with no PAINS, Brenk, or lead-likeness violations, ensuring high chemical stability and reduced risk of non-specific interactions. At a non-toxic concentration, tricin exerted significant anti-migration effects by targeting ADAMTS1 in OSCC and RCC cells We further investigated whether tricin, identified as the compound with the highest affinity for ADAMTS1, could inhibit its function in cancer. Our previous studies demonstrated that ADAMTS1 promotes OSCC tumor metastasis, with EGFR identified as a key downstream target involved in its pro-metastatic activity [ 9 ]. A Western blot analysis revealed that OSCC cell lines, including HSC-3, HSC-3M, and SAS, expressed relatively higher levels of ADAMTS1 compared to SCC9 cells (Fig. 2 A). Notably, tricin treatment at 6.25 and 12.5 µM resulted in marked downregulation of ADAMTS1 and EGFR in HSC-3M and SAS cells (Fig. 2 B), suggesting that tricin broadly suppresses the ADAMTS1-EGFR signaling axis in OSCC cells. Functionally, significant anti-migratory effects of tricin at 6.25 and 12.5 µM after 24 h of treatment were observed in SAS and HSC-3M cells, but not in SCC9 cells (Fig. 2 C), suggesting that tricin selectively inhibits migration in OSCC cells with high ADAMTS1 expression. Furthermore, ADAMTS1 overexpression significantly reversed the migration inhibition caused by tricin treatment in HSC-3 cells (Fig. 2 D). To rule out the possibility that the reduced number of migrating cells was due to decreased cell viability, we performed a CCK-8 assay on SAS and HSC-3M cells treated with the same concentrations of tricin for an extended period (72 h). Both 6.25 and 12.5 µM tricin showed minimal cytotoxicity in SAS cells, with no significant effect on HSC-3M cells (Fig. 2 E). Collectively, these results suggest that tricin, at non-cytotoxic concentrations, impairs the motility of OSCC cells by targeting ADAMTS1. In addition to OSCC, the oncogenic role of the ADAMTS1-EGFR axis was also validated in RCC [ 10 , 25 ]. A Western blot analysis from our previous study indicated that RCC cell lines, including Caki-1, 786-O, and Achn, expressed relatively higher levels of ADAMTS1 compared to A498 cells [ 25 ]. Tricin treatment predominantly inhibited expression of the ADAMTS1-EGFR axis in both Caki-1 and 786-O cells (Fig. 3 A). Moreover, a significant anti-migratory effect of tricin was observed in RCC cells (786-O and Caki-1) with high ADAMTS1 expression, but not in A498 cells, which expressed very low levels of ADAMTS1 (Fig. 3 B). Additionally, only 12.5 µM tricin exhibited minimal cytotoxicity in 786-O cells, with no significant effect observed in Caki-1 cells (Fig. 3 C). Similar to the findings in OSCC, non-toxic concentrations of tricin were also able to suppress the motility of RCC cells by targeting ADAMTS1. At a non-toxic concentration, tricin exerts significant anti-adhesive effects by targeting ADAMTS1 in OSCC and RCC cells In addition to cell motility, the adhesive ability of cancer cells is also critical for metastasis [ 26 ]. ADAMTS1 was reported to enhance the adhesive capacity of breast cancer cells [ 27 ]. In this study, manipulation of ADAMTS1 expression affected the migratory capacity of SAS, HSC-3M, and 786-O cells in a transwell migration assay (Fig. 4 A), but had no effect on wound closure in a wound-healing assay (Fig. 4 B), suggesting that adhesion may be a key mechanism through which ADAMTS1 influences cancer cell motility. Clinically, a strong correlation was observed between ADAMTS1 expression and a focal adhesion-related gene signature in human ccRCC and HNSCC samples obtained from TCGA database (Fig. 4 C). Notably, knockdown of ADAMTS1 significantly reduced the adhesive abilities of various RCC (Caki-1 and 786-O) and OSCC (SAS and HSC-3M) cell lines (Fig. 4 D). Furthermore, treatment of RCC and OSCC cells with different concentrations of tricin markedly attenuated their adhesive properties (Fig. 4 E, right panel). With increasing tricin concentrations, OSCC and RCC cells that exhibited a spread, adhesive morphology (indicated by red arrows) transitioned to a more-rounded, less-adhesive phenotype (Fig. 4 E, left panel). In contrast, the inhibitory effect of tricin on cell adhesion was not observed in A498 cells, which express very low levels of ADAMTS1 (Fig. S1 ). Overexpression of ADAMTS1 in HSC-3 cells significantly reversed the tricin-induced inhibition of adhesion (Fig. 4 F), suggesting that tricin selectively inhibits the adhesive ability of cancer cells with high ADAMTS1 expression. FAK and Src, two tyrosine kinases that are part of the focal adhesion-related gene signature described above, play critical roles in cell adhesion and migration, particularly in the context of cancer [ 28 ]. In this study, we found that tricin treatment also suppressed activation of FAK and Src in HSC-3M and Caki-1 cells, as indicated by downregulation of p-FAK (Tyr397) and p-Src (Tyr416) (Fig. 4 G). Discussion Results of our research provide encouraging evidence supporting ADAMTS1 inhibitors as potential drug candidates for cancer treatment. Through molecular docking and ADMET predictions, we identified several small molecules—particularly tricin—that exhibited potential inhibitory activity against ADAMTS1, a key player in cancer progression [ 11 ]. Tricin’s binding to ADAMTS1 with the strongest binding affinity of − 10.93 kcal/mol suggests that it could be a highly effective inhibitor, altering the protein structure and blocking its activity in ECM remodeling, which is essential for tumor metastasis. Our previous studies demonstrated that the ADAMTS1-EGFR axis is critical for promoting several steps in tumor metastasis, including motility and resistance to anoikis in OSCC and RCC [ 9 , 10 , 25 ]. In vivo, we found that ADAMTS1 overexpression significantly promoted tumor metastasis of RCC and OSCC in zebrafish xenograft and mouse orthotopic xenograft models [ 9 , 10 , 25 ]. In the present study, our in vitro assays demonstrated that tricin treatment suppressed expression of the ADAMTS1-EGFR axis in OSCC and RCC cells. Tricin effectively inhibited the migratory and adhesive capacities of both cancer types, particularly in cell lines with high ADAMTS1 expression. FAK and Src are critical regulators of cancer cell adhesion and migration, and EGFR/Src signaling was reported to activate FAK in cancers [ 29 ]. We observed that tricin also inhibited activation of both Src and FAK in OSCC and RCC cells, suggesting that this effect may result from tricin-induced suppression of the ADAMTS1-EGFR axis. Moreover, our previous study demonstrated that apigenin functions as a potential inhibitor of the ADAMTS1-EGFR axis and effectively suppresses ADAMTS1-induced enhancement of in vitro invasion and in vivo lymph node metastasis in OSCC [ 9 ]. Apigenin and tricin, flavones respectively found in leafy vegetables and rice bran, share similar structures: tricin (4’,5,7-trihydroxy-3’,5’-dimethoxyflavone) is closely related to apigenin (4’,5,7-trihydroxyflavone). A previous study reported that when administered to mice through the diet, tricin levels in plasma, the liver, and mucosa exceeded those of apigenin by 350%, 33%, and 100%, respectively. These findings suggest that tricin has greater in vivo bioavailability compared to apigenin [ 30 ]. Therefore, tricin may possess a PK advantage over apigenin, suggesting it may exhibit a more-potent anti-metastatic effect in OSCC and RCC. Taken together, these findings suggest that tricin may serve as a potential anti-metastatic agent in specific cancer types characterized by high ADAMTS1 expression. The active site region of ADAMTS1, characterized by the catalytic zinc-binding motif (ZN 401) and surrounding residues (Thr117, Leu118, Ile120, His149, His153, His159, and Met177), was described in structural and functional studies of ADAMTS family proteins [ 31 ]. The molecular docking analysis showed that tricin had a higher binding score than other potential screened compounds, such as dichotomitin, belamcandin, and wogonin. The observed metal coordination with tricin supports the role of the catalytic zinc ion (Zn²⁺) in stabilizing ligand binding, a characteristic feature of ADAMTS metalloproteinases. These findings reinforce the specificity of binding within the active site and highlight the therapeutic potential of these small molecules as ADAMTS1 inhibitors. These highlight their potential as promising candidates for future cancer therapies. SwissADME PK profiling also confirmed the drug-likeness of tricin, dichotomitin, belamcandin, wogonin, and feralolide. All compounds passed major filters such as the Lipinski, Ghose, Veber, Egan, and Muegge rules without any violations and showed a consistent bioavailability score of 0.55. Furthermore, no PAINS or Brenk alerts were detected, indicating a low risk of toxicity or reactivity. Only dichotomitin and belamcandin exhibited one lead-likeness violation each, which may limit their use in early drug discovery. In terms of PKs, all compounds showed high human HIA, suggesting that they are potentially orally bioavailable. Predictions of other ADMET properties for these candidate compounds also revealed favorable PK profiles, further supporting their potential for development as drug candidates. These findings highlight the therapeutic promise of natural and synthetic inhibitors of ADAMTS1 for cancer treatment. However, despite computational studies providing valuable data, experimental confirmation with in vivo models is required to determine the effectiveness and safety of these molecules. Further studies are also needed to explore the specific mechanisms by which these inhibitors control ADAMTS1 expression and influence the overall TME, particularly in relation to metastasis. In this study, a comprehensive computational approach was used to identify and evaluate potential inhibitors of ADAMTS1, an important enzyme involved in cancer progression. Molecular docking results recognized tricin as the lead compound with optimal binding affinity along with favorable PK properties, making it an appropriate candidate for further preclinical development. Moreover, results from functional assays indicated the possibility of tricin being a candidate for cancer treatment in the future, particularly as more-effective treatments for ADAMTS1-enriched cancer types (Fig. 5 ). Lastly, our findings also revealed several other compounds with potential inhibitory effects on ADAMTS1, suggesting that ADAMTS1 inhibition by small-molecule inhibitors could be a novel therapeutic strategy for managing aggressive cancers. Abbreviations ADAMTS1 a disintegrin and metalloproteinase with thrombospondin motifs 1 ADMET absorption,distribution,metabolism,excretion,and toxicity OSCC oral squamous cell carcinoma ccRCC clear cell renal cell carcinoma EGFR epidermal growth factor receptor FAK focal adhesion kinase SMILES Simplified Molecular Input Line Entry System PAINS Pan-Assay Interference Compounds TCGA The Cancer Genome Atlas ssGSEA single-sample gene set enrichment analysis GO Gene Ontology PK pharmacokinetic CYP cytochrome P450 CCK-8 Cell Counting Kit-8. Declarations Consent for publication Not applicable. Conflicts of interest No author declared any conflicts of interest. Acknowledgments Not applicable. Authors’ contributions AS, CHL, and MHC designed and conceived the study. MCT and MHC supervised the study. AS and SG contribute to the molecular docking and ADMET analysis. CHL, YWL, and YCW performed the in vitro experiments and acquired the data. YCY, WJL, and MHC contributed to the bioinformatic analysis and statistical analyses. MHC and MCT wrote and revised the manuscript. All authors reviewed the results and agreed to the published version of the manuscript. Funding This work was supported by the Research Center of Cancer Translational Medicine at Taipei Medical University, under the Featured Areas Research Center Program of the Higher Education Sprout Project, Ministry of Education, Taiwan (awarded to M.-H.C.). Additional support was provided by Wan Fang Hospital, Taipei Medical University (grant no. 113TMU-WFH-01, awarded to Y.-C.W.). Data Availability Statement All data supporting the findings of this study are included in the article. Original datasets are available from the corresponding author upon reasonable request. References Wang, Z., et al., Role of ADAM and ADAMTS proteases in pathological tissue remodeling. Cell Death Discov, 2023. 9 (1): p. 447. Bacchetti, R., S. Yuan, and E. Rainero, ADAMTS Proteases: Their Multifaceted Role in the Regulation of Cancer Metastasis. Dis Res, 2024. 4 (1): p. 40-52. Szmajda-Krygier, D., et al., Assessment of Methylation in Selected ADAMTS Family Genes in Non-Small-Cell Lung Cancer. Int J Mol Sci, 2025. 26 (3). Cal, S. and C. López-Otín, ADAMTS proteases and cancer. Matrix Biol, 2015. 44-46 : p. 77-85. Kumar, S., N. Rao, and R. Ge, Emerging Roles of ADAMTSs in Angiogenesis and Cancer. Cancers (Basel), 2012. 4 (4): p. 1252-99. Hu, X., et al., ADAMTS1 induces epithelial-mesenchymal transition pathway in non-small cell lung cancer by regulating TGF-β. Aging (Albany NY), 2023. 15 (6): p. 2097-2114. Rocks, N., et al., ADAMTS-1 metalloproteinase promotes tumor development through the induction of a stromal reaction in vivo. Cancer Res, 2008. 68 (22): p. 9541-50. Redondo-García, S., et al., ADAMTS proteases and the tumor immune microenvironment: Lessons from substrates and pathologies. Matrix Biol Plus, 2021. 9 : p. 100054. Chien, M.H., et al., Cyclic increase in the ADAMTS1-L1CAM-EGFR axis promotes the EMT and cervical lymph node metastasis of oral squamous cell carcinoma. Cell Death Dis, 2024. 15 (1): p. 82. Wen, Y.C., et al., The oncogenic ADAMTS1-VCAN-EGFR cyclic axis drives anoikis resistance and invasion in renal cell carcinoma. Cell Mol Biol Lett, 2024. 29 (1): p. 126. Tan Ide, A., C. Ricciardelli, and D.L. Russell, The metalloproteinase ADAMTS1: a comprehensive review of its role in tumorigenic and metastatic pathways. Int J Cancer, 2013. 133 (10): p. 2263-76. Khan, S.U., K. Fatima, and F. Malik, Understanding the cell survival mechanism of anoikis-resistant cancer cells during different steps of metastasis. Clin Exp Metastasis, 2022. 39 (5): p. 715-726. Davies, C.R., et al., The potential of using circulating tumour cells and their gene expression to predict docetaxel response in metastatic prostate cancer. Front Oncol, 2022. 12 : p. 1060864. Wang, S., et al., ADAMTS1 as potential prognostic biomarker promotes malignant invasion of glioma. Int J Clin Oncol, 2023. 28 (1): p. 52-68. Hirano, T., et al., Inhibition of tumor growth by antibody to ADAMTS1 in mouse xenografts of breast cancer. Anticancer Res, 2011. 31 (11): p. 3839-42. Pluda, S., Y. Mazzocato, and A. Angelini, Peptide-Based Inhibitors of ADAM and ADAMTS Metalloproteinases. Front Mol Biosci, 2021. 8 : p. 703715. Daina, A., O. Michielin, and V. Zoete, SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep, 2017. 7 : p. 42717. Morris, G.M., et al., AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem, 2009. 30 (16): p. 2785-91. Li, H., et al., Improving AutoDock Vina Using Random Forest: The Growing Accuracy of Binding Affinity Prediction by the Effective Exploitation of Larger Data Sets. Mol Inform, 2015. 34 (2-3): p. 115-26. Trott, O. and A.J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem, 2010. 31 (2): p. 455-61. Sakhawat, A., et al., Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis. AMB Express, 2023. 13 (1): p. 134. Tseng, T.H., et al., Inhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21(WAF1/CIP1) expression. Environ Toxicol, 2017. 32 (2): p. 434-444. Chien, M.H., et al., Targeting the SPOCK1-snail/slug axis-mediated epithelial-to-mesenchymal transition by apigenin contributes to repression of prostate cancer metastasis. J Exp Clin Cancer Res, 2019. 38 (1): p. 246. Lin, Y.W., et al., Stabilization of ADAM9 by N-α-acetyltransferase 10 protein contributes to promoting progression of androgen-independent prostate cancer. Cell Death Dis, 2020. 11 (7): p. 591. Wen, Y.C., et al., Melatonin-triggered post-transcriptional and post-translational modifications of ADAMTS1 coordinately retard tumorigenesis and metastasis of renal cell carcinoma. J Pineal Res, 2020. 69 (2): p. e12668. Yayan, J., et al., Adhesion, metastasis, and inhibition of cancer cells: a comprehensive review. Mol Biol Rep, 2024. 51 (1): p. 165. Tan, I.A., et al., ADAMTS1 Promotes Adhesion to Extracellular Matrix Proteins and Predicts Prognosis in Early Stage Breast Cancer Patients. Cell Physiol Biochem, 2019. 52 (6): p. 1553-1568. Bolós, V., et al., The dual kinase complex FAK-Src as a promising therapeutic target in cancer. Onco Targets Ther, 2010. 3 : p. 83-97. Tai, Y.L., et al., An EGFR/Src-dependent β4 integrin/FAK complex contributes to malignancy of breast cancer. Sci Rep, 2015. 5 : p. 16408. Cai, H., et al., Tissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties. Cancer Chemother Pharmacol, 2007. 60 (2): p. 257-66. De Savi, C., et al., The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis. Bioorg Med Chem Lett, 2011. 21 (5): p. 1376-81. 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The figure presents the interactions of the ligands—tricin (\u003cstrong\u003eA\u003c/strong\u003e, \u003cstrong\u003eB\u003c/strong\u003e), dichotomitin (\u003cstrong\u003eC\u003c/strong\u003e, \u003cstrong\u003eD\u003c/strong\u003e), belamcandin (\u003cstrong\u003eE\u003c/strong\u003e, \u003cstrong\u003eF\u003c/strong\u003e), wogonin (\u003cstrong\u003eG\u003c/strong\u003e, \u003cstrong\u003eH\u003c/strong\u003e), feralolide (\u003cstrong\u003eI\u003c/strong\u003e, \u003cstrong\u003eJ\u003c/strong\u003e), and quantitative functional group (QFG) (\u003cstrong\u003eK\u003c/strong\u003e, \u003cstrong\u003eL\u003c/strong\u003e)—with the ADAMTS1 protein. \u003cstrong\u003eM \u003c/strong\u003eAll docked ligands were superimposed with QFG.\u003c/p\u003e","description":"","filename":"Figure1V1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7521823/v1/82da22e2a1a68cf8baf2f887.jpg"},{"id":91599047,"identity":"d2e8e1dc-ad6e-49c4-9af8-191d87403883","added_by":"auto","created_at":"2025-09-18 08:17:20","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":564747,"visible":true,"origin":"","legend":"\u003cp\u003eTricin targeting ADAMTS1 effectively suppressed the migratory ability of oral squamous cell carcinoma (OSCC) cells.\u003cstrong\u003e A \u003c/strong\u003eWestern blot analysis was performed to detect endogenous protein levels of ADAMTS1 in OSCC cell lines, including HSC-3, HSC-3M, SCC9, and SAS. \u003cstrong\u003eB\u003c/strong\u003e, \u003cstrong\u003eC \u003c/strong\u003eHSC-3M, SAS, and SCC9 cells were treated with the indicated concentrations of tricin for 24 h. ADAMTS1 and EGFR expression levels and cell-migratory abilities were respectively assessed by a Western blot analysis (\u003cstrong\u003eB\u003c/strong\u003e) and transwell migration assays (\u003cstrong\u003eC\u003c/strong\u003e). \u003cstrong\u003eD\u003c/strong\u003e HSC-3 cells were transiently transfected with a vector control or ADAMTS1-flag followed by tricin or vehicle treatment for an additional 24 h. The migratory abilities of cells were further measured. \u003cstrong\u003eC\u003c/strong\u003e, \u003cstrong\u003eD\u003c/strong\u003e Representative photographs of migrated cells (left panel) and quantification of those cells (right panel). Data are presented as the mean ± SD, *** \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001 vs. vehicle control cells and \u003csup\u003e### \u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, vs. cells only treated with tricin. n.s., not significant. \u003cstrong\u003eE\u003c/strong\u003e OSCC cells were exposed to different concentrations of tricin for 72 h, followed by an assessment of cell viability using a Cell Counting Kit‑8 assay. ** \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01 and *** \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001 vs. the vehicle control group.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7521823/v1/47dff82d857039ac32f8fb57.jpg"},{"id":91598610,"identity":"aef39776-fc0a-4123-a8a4-a69b0993118f","added_by":"auto","created_at":"2025-09-18 08:09:13","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":440678,"visible":true,"origin":"","legend":"\u003cp\u003eHigher ADAMTS1 expression correlates with a stronger anti-migratory effect of tricin in renal cell carcinoma (RCC) cells. \u003cstrong\u003eA\u003c/strong\u003e Caki-1 and 786-O cells were treated with tricin for 24 h, and levels of ADAMTS1 and EGFR proteins were assessed through a Western blot analysis. \u003cstrong\u003eB\u003c/strong\u003e786-O, Caki-1, and A498 cells were treated with the indicated concentrations of tricin for 24 h, and cell-migratory abilities were assessed using a transwell migration assay. Representative images of migrated cells are shown (left panel), along with their quantification (right panel). Data are presented as the mean ± SD. * \u003cem\u003ep\u003c/em\u003e\u0026lt; 0.05, ** \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01 compared to the control group; n.s., not significant. \u003cstrong\u003eC\u003c/strong\u003eRCC cells were treated with different concentrations of tricin for 72 h, followed by a cell viability assessment using the CCK-8 assay. ** \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01 vs. the vehicle control.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7521823/v1/b3ce52ce94128a3fff7c6832.jpg"},{"id":91598614,"identity":"e83892f9-a0a4-47de-9548-e6a014a7e687","added_by":"auto","created_at":"2025-09-18 08:09:16","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1209337,"visible":true,"origin":"","legend":"\u003cp\u003eADAMTS1 plays a key role in the adhesive ability of RCC and OSCC cells, and this process can be suppressed by tricin. \u003cstrong\u003eA\u003c/strong\u003e 786-O, Caki-1, and SAS cells were infected with a lentivirus carrying either ADAMTS1-Flag or ADAMTS1 shRNA and subjected to a transwell migration assay. Representative images of migrated cells are shown (upper panel), along with their quantification (lower panel). Data are presented as the mean ± SD. * \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05, *** \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001 compared to the control group. \u003cstrong\u003eB\u003c/strong\u003e The motility of ADAMTS1-knockdown Caki-1 cells was examined using a wound-healing assay. Cells were wounded and cultured for 24 h, and the wound areas were observed under phase-contrast microscopy. \u003cstrong\u003eC\u003c/strong\u003e Correlations between \u003cem\u003eADAMTS1\u003c/em\u003e gene expression and focal adhesion-related gene signatures were analyzed using RNA sequencing data from TCGA head and neck squamous cell carcinoma (HNSCC) and kidney renal clear cell carcinoma (KIRC) patients. Correlation coefficients and \u003cem\u003ep\u003c/em\u003e values were calculated using a Pearson correlation analysis. \u003cstrong\u003eD\u003c/strong\u003e, \u003cstrong\u003eE \u003c/strong\u003eRCC (786-O and Caki-1) and OSCC (SAS and HSC-3M) cells were either stably knocked down for ADAMTS1 (\u003cstrong\u003eD\u003c/strong\u003e) or treated with various concentrations of tricin for 24 h (\u003cstrong\u003eE\u003c/strong\u003e), then subjected to an adhesion assay. Morphological changes in adherent cells were observed using phase-contrast microscopy (left panel in \u003cstrong\u003eE\u003c/strong\u003e). Data are presented as the mean ± SD. * \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05, ** \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01, *** \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001 compared to the control group. (\u003cstrong\u003eF\u003c/strong\u003e) HSC-3 cells were transiently transfected with a vector control or ADAMTS1-flag followed by tricin or vehicle treatment for an additional 24 h. The adhesive abilities of cells were further measured. Representative photographs of adhesive cells (left panel) and quantification of those cells (right panel). Data are presented as the mean ± SD, *** \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001 vs. vehicle control cells and\u003csup\u003e ### \u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, vs. tricin-treated only cells. (\u003cstrong\u003eG\u003c/strong\u003e) HSC-3M and Caki-1 cells were treated with indicated concentrations of tricin for 24 h. Phosphorylated (p)-FAK and p-Src levels were assessed by a Western blot analysis.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7521823/v1/faf16fc6342f5a810ae44c1e.jpg"},{"id":91599031,"identity":"22ea00fa-f7a5-4fa7-b142-8192dc0556a7","added_by":"auto","created_at":"2025-09-18 08:17:18","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":102015,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic illustration depicting the comprehensive computational approach used to identify tricin as a potential inhibitor of ADAMTS1 and to evaluate its antimetastatic effects in ADAMTS1-enriched cancers.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7521823/v1/1eecbf4eb44dcbc7db1232e1.jpg"},{"id":92634376,"identity":"164baced-399d-4642-b4bc-6c112e8197e3","added_by":"auto","created_at":"2025-10-02 05:12:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4976857,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7521823/v1/a3d609f1-55b2-4a74-b790-4373ca68010e.pdf"},{"id":91598634,"identity":"0ecd73de-4a42-4fff-bcb3-082aa8edc0b6","added_by":"auto","created_at":"2025-09-18 08:09:20","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":176439,"visible":true,"origin":"","legend":"","description":"","filename":"SupportinginformationCellBiosciencefinalver..docx","url":"https://assets-eu.researchsquare.com/files/rs-7521823/v1/c31e298bbea974b66a4201ce.docx"}],"financialInterests":"","formattedTitle":"Discovery of tricin as a novel ADAMTS1 inhibitor via molecular docking and ADMET predictions for inhibiting cancer metastasis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the ADAMTS family\u0026mdash;a group of secreted enzymes that play important roles in remodeling the extracellular matrix (ECM) and regulating cellular interactions with the matrix [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These enzymes contribute to various physiological processes, including tissue homeostasis, wound healing, and the pathogenesis of several diseases, including inflammatory disorders, cardiovascular diseases, and cancers [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. ADAMTS1, in particular, was shown to exert tumor-promoting functions, positioning it as a key player in the complex biology of cancer [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDuring tumorigenesis, the expression and activity of ADAMTS1 are often altered, leading to significant changes in the tumor microenvironment (TME) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In various types of cancers, including renal cell carcinoma (RCC), oral squamous cell carcinoma (OSCC), and breast and other cancers, ADAMTS1 expression was linked to tumor progression, metastasis, and a poor prognosis [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The multifaceted role of ADAMTS1 in cancer is attributed to its ability to interact with various substrates, including ECM components such as versican (VCAN) and matrix metalloproteinases (MMPs), and its involvement in signaling pathways critical for tumor growth and spread [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For example, ADAMTS1 was shown to regulate anoikis, a type of programmed cell death that occurs when cells detach from the ECM. In RCC, ADAMTS1 contributes to anoikis resistance by activating key signaling pathways, such as the VCAN-epidermal growth factor receptor (EGFR) axis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and this axis reinforces ADAMTS1 expression through positive feedback. This resistance is a critical factor that enables cancer cells to survive while in circulation, thereby facilitating metastasis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Moreover, ADAMTS1 plays a critical role in promoting the epithelial-to-mesenchymal transition (EMT), a process that endows cancer cells with enhanced migratory and invasive capabilities [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In OSCC, ADAMTS1 was shown to regulate the ADAMTS1-L1 cell adhesion molecule (L1CAM)-EGFR signaling axis, thereby facilitating the EMT and contributing to lymph node metastasis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In non-small cell lung cancer (NSCLC), ADAMTS1 was reported to induce an EMT pathway via regulating transforming growth factor (TGF)-β [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In metastatic prostate cancer, expressions of ADAMTS1 and EMT-related markers, such as zinc finger E-box-binding homeobox 1 (ZEB1) and snail family transcription repressor 1 (SNAI1), were significantly associated with a poor prognosis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Moreover, ADAMTS1 was reported to affect the invasive phenotype of glioma stem cells by regulating the Notch1-SRY box 2 (SOX2) signaling pathway [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These findings further highlight the role of ADAMTS1 in driving cancer cell metastasis, particularly in aggressive tumor types.\u003c/p\u003e\u003cp\u003eGiven the critical role of ADAMTS1 in cancer progression\u0026mdash;regulating key processes such as cell stemness, adhesion, invasion, metastasis, and ECM remodeling\u0026mdash;its inhibition represents a promising strategy for anticancer therapy. For instance, Hirano et al. demonstrated that antibody-mediated blockade of ADAMTS1 effectively suppressed breast cancer growth in a mouse model [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Some peptide-based inhibitors against ADAMTS1 were reported [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, specific small-molecule inhibitors targeting ADAMTS1 are not yet available. In this study, we employed molecular docking and pharmacokinetic analyses to identify potential small-molecule inhibitors of ADAMTS1. In total, 30 compounds including isoflavonoids, flavones, alkaloids, and rare or less-studied phytochemicals were sourced from traditional Chinese medicinal herbs. These natural and synthetic compounds were subjected to virtual screening using ADMET profiling and AutoDock Vina. Promising hit compounds identified through an \u003cem\u003ein silico\u003c/em\u003e analysis were subsequently evaluated through functional assays to confirm their inhibitory potential against ADAMTS1.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eAbsorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions using SwissADME\u003c/h2\u003e\u003cp\u003eInitially, SMILES (Simplified Molecular Input Line Entry System) representations of 30 compounds were retrieved from PubChem (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubchem.ncbi.nlm.nih.gov\u003c/span\u003e\u003cspan address=\"https://pubchem.ncbi.nlm.nih.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). These compounds were then analyzed using SwissADME (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.swissadme.ch/\u003c/span\u003e\u003cspan address=\"http://www.swissadme.ch/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to evaluate their pharmacokinetic (PK) and pharmacodynamic properties, including ADMET. Assessing these parameters is essential for understanding the drug-likeness and therapeutic potential of the compounds [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This analysis used various parameters, including physicochemical properties, lipophilicity, water solubility, PKs, drug-likeness, and medicinal chemistry aspects. Physicochemical descriptors such as molecular weight (MW), molecular refractivity (MR), the count of specific atom types, and polar surface area (PSA) were assessed. The PSA was calculated using the topological PSA (TPSA) method, which considers sulfur and phosphorus as polar atoms. This descriptor helps estimate ADMET properties, particularly related to absorption and blood-brain barrier (BBB) penetration.\u003c/p\u003e\u003cp\u003eAnother important descriptor is the partition coefficient, used to calculate lipophilicity, which is essential for predicting the PKs of a molecule. Water solubility is also a key factor, especially for drugs intended for oral administration, as solubility greatly influences absorption. For parenteral administration, high solubility in water is necessary to ensure that an adequate dose can be delivered in a small volume. The PK section includes predictions for passive human intestinal absorption (HIA) and BBB permeability, as well as identification of compounds as substrates or non-substrates of P-glycoprotein (Pgp). It also evaluates potential interactions with cytochrome P450 (CYP) enzymes, which are important for assessing drug-drug interactions and risks of toxicity due to reduced drug clearance or metabolite accumulation.\u003c/p\u003e\u003cp\u003eThe drug-likeness of compounds was assessed using multiple rules: Lipinski, Ghose, Veber, Egan, and Muegge. These filters were developed by pharmaceutical companies to evaluate the structural and physicochemical suitability of compounds as oral drug candidates. Compounds violating any of these rules were flagged. Additionally, the Abbott Bioavailability Score was used to estimate the probability of a compound achieving at least 10% oral bioavailability, based on factors such as the total charge and TPSA. This comprehensive screening helped identify compounds with favorable PK profiles.\u003c/p\u003e\u003cp\u003eTo ensure the overall safety, stability, and drug development potential of the selected compounds, further evaluations were conducted using the Medicinal Chemistry section of the SwissADME platform. Compounds were screened for structural risks using two filters: PAINS (Pan-Assay Interference Compounds), which identifies substructures that may cause false-positive biological results, and Brenk alerts, which detect potentially toxic or unstable fragments. Additionally, compounds were evaluated for lead-likeness to determine their suitability for further chemical optimization, focusing on appropriate size and lipophilicity. Together, these evaluations helped prioritize the most promising compounds for further experimental validation. Compounds that showed no Lipinski violations were subjected to a molecular docking analysis to analyze binding of the shrink database.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePreparation of protein and ligands\u003c/h3\u003e\n\u003cp\u003eThe crystal structure of ADAMTS1 was prepared for molecular docking studies using MGL Tools vers. 1.5.6 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ccsb.scripps.edu/mgltools/downloads/\u003c/span\u003e\u003cspan address=\"https://ccsb.scripps.edu/mgltools/downloads/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Protein preparation involved several key steps to ensure its stability and suitability for a docking analysis. Initially, during protein preparation, only those water molecules located within 3 \u0026Aring; of the co-crystallized ligand were retained, as they may play a critical role in stabilizing ligand interactions through hydrogen bonding or bridging effects. All other water molecules were removed to reduce noise and improve the accuracy of the docking results. Subsequently, polar hydrogen atoms were added to the protein structure to account for hydrogen bonding interactions, and partial Kollman charges were assigned to optimize the electrostatic environment of the active site. Further, the protein was converted into PDBQT format required for AutoDock-based docking studies [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFollowing protein preparation, grid generation was performed to define the docking region. The grid box was centered on the active site of ADAMTS, corresponding to the binding site of the reference inhibitor quantitative functional group (QFG). The grid box was set with dimensions of 24 \u0026times; 24 \u0026times; 24 \u0026Aring; along the x-, y-, and z-axes, respectively, with a spacing of 1 \u0026Aring;, providing a comprehensive search space for ligand binding during the docking process. The Grid box was generated on supplied coordinates of x\u0026thinsp;=\u0026thinsp;10.15, y=-12.98, and z\u0026thinsp;=\u0026thinsp;10.31.\u003c/p\u003e\u003cp\u003eLigand molecules were initially designed and sketched using ChemDraw software. These two-dimensional (2D) structures were then imported into Chem3D for three-dimensional (3D) conversion and geometric optimization. Energy minimization of the ligands was carried out using the MMFF94 (Merck Molecular Force Field) force field, with an root mean square (RMS) gradient convergence criterion set to 0.001 to ensure a stable and low-energy conformation. After minimization, ligand structures were saved in protein data bank (PDB) format and further processed in MGL Tools 1.5.6 for docking, including the addition of Gasteiger charges, identification of torsional bonds, and conversion into the PDBQT format required for AutoDock-based docking studies.\u003c/p\u003e\n\u003ch3\u003eMolecular docking\u003c/h3\u003e\n\u003cp\u003eMolecular docking was carried out using AutoDock Vina [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] to study how the selected ligands bound to the target protein, ADAMTS1 (PDB ID: 3Q2G). The docking focused on the active site of the protein to ensure that the ligands interacted with the important region responsible for its function. In this process, the protein structure was kept fixed, while the ligands were allowed to move and change shape to fit into the binding site. For each ligand, nine possible binding positions were generated, and their binding strengths were measured. Results were ranked based on the binding energy, where lower values showed stronger and more-stable interactions. To check the accuracy of the results, the compounds were docked again, and the RMS deviation (RMSD) was calculated. Docking results were also viewed to see how the ligands and protein interacted. This helped in choosing the most suitable compounds for further testing, including studies on their safety and effectiveness.\u003c/p\u003e\n\u003ch3\u003eVisualization of binding interactions\u003c/h3\u003e\n\u003cp\u003eTo further analyze molecular interactions between ADAMTS1 and docked ligands, Discovery Studio Visualizer (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.3ds.com/products/biovia\u003c/span\u003e\u003cspan address=\"https://www.3ds.com/products/biovia\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] was used to identify hydrogen bonds, hydrophobic interactions, van der Waals forces, and π\u0026ndash;π stacking interactions. These interactions are critical for evaluating the stability and specificity of ligand binding. In addition, PyMOL (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.pymol.org/\u003c/span\u003e\u003cspan address=\"https://www.pymol.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] was employed for 3D visualization of the docked complexes, allowing for detailed examination of each ligand\u0026rsquo;s orientation within ADAMTS1\u0026rsquo;s active site. This visualization provides valuable insights into how the structural features of the ligands influence their binding affinity and conformational stability. Understanding these interactions is essential for selecting lead compounds with strong potential for further biological validation and drug development. Compounds that showed hits and proper binding interactions with ADAMTS1 were used for further analysis.\u003c/p\u003e\n\u003ch3\u003eMaterials\u003c/h3\u003e\n\u003cp\u003eTricin (HY-N1127) was obtained from MedChemExpress (Monmouth Junction, NJ, USA). Fetal bovine serum (FBS), antibiotics, molecular weight (MW) markers, trypsin-EDTA, and other medium supplements were sourced from Life Technologies (Gaithersburg, MD, USA). The pLEX-MCS-ADAMTS1 expression construct was kindly provided by Dr. T.C. Kuo (National Taiwan University, Taipei, Taiwan). Antibodies against ADAMTS1 (AF5867) and GAPDH (60004-1-Ig) were respectively purchased from R\u0026amp;D Systems (Minneapolis, MN, USA) and Proteintech Group (Chicago, IL, USA). Antibodies against epidermal growth factor receptor (EGFR; #4267), phosphorylated (p)-focal adhesion kinase (FAK; #3281), and p-Src (#2101) were obtained from Cell Signaling Technology (Danvers, MA, USA).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eCell lines and cell culture\u003c/h2\u003e\u003cp\u003eHuman OSCC cell lines\u0026mdash;SAS, HSC-3, HSC-3M, and SCC9\u0026mdash;were obtained from the Japanese Collection of Research Bioresources (JCRB) Cell Bank (Osaka, Japan), while the RCC cell lines\u0026mdash;Caki-1, 786-O, and A498\u0026mdash;were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA). SAS and SCC9 cells were cultured in Dulbecco\u0026rsquo;s modified Eagle medium/Nutrient Mixture F-12 (DMEM/F-12; Gibco, Grand Island, NY, USA), whereas HSC-3, HSC-3M, Caki-1, and A498 cells were maintained in minimum essential medium (MEM; Gibco). 786-O cells were cultured in RPMI-1640 medium. All media were supplemented with 10% fetal bovine serum (FBS) and 100 U/mL penicillin-streptomycin. Cells were incubated at 37\u0026deg;C in a humidified atmosphere containing 5% CO\u003csub\u003e2\u003c/sub\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eWestern blot assay\u003c/h3\u003e\n\u003cp\u003eTotal cell lysates were prepared and quantified as previously described [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Proteins (30\u0026ndash;50 \u0026micro;g) were resolved by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidene difluoride (PVDF) membranes (Merck Millipore, Burlington, MA, USA). Membranes were probed with primary and horseradish peroxidase (HRP)-conjugated secondary antibodies, then visualized using an enhanced chemiluminescence (ECL) reagent (TOOLS, New Taipei City, Taiwan). Chemiluminescence was detected with the MultiGel-21 imaging system (TOP BIO, New Taipei City, Taiwan).\u003c/p\u003e\n\u003ch3\u003eCell viability assay\u003c/h3\u003e\n\u003cp\u003eAfter treating OSCC and ccRCC cells with various concentrations of tricin for either 24 or 72 h, 5000 cells were seeded into individual wells of a 96-well plate. Cell viability was assessed by adding 100 \u0026micro;l of medium containing 10% Cell Counting Kit-8 (CCK-8; cat. no. 96992; MilliporeSigma, Rockville, MD, USA) to each well. The assay was conducted at 37\u0026deg;C, and the absorbance at 450 nm was measured hourly for up to 4 h.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eTranswell migration assay\u003c/h2\u003e\u003cp\u003eThe \u003cem\u003ein vitro\u003c/em\u003e migratory ability of cancer cells was assessed as previously described [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Briefly, (5\u0026ndash;8) \u0026times; 10\u003csup\u003e4\u003c/sup\u003e OSCC or RCC cells were seeded into the upper chamber of a transwell insert (24-well; 8-\u0026micro;m pore size; Corning Costar, Corning, NY, USA) containing serum-free medium, with or without candidate compounds at the indicated concentrations. The lower chamber was filled with medium supplemented with 10% FBS as a chemoattractant. After 24 h incubation at 37\u0026deg;C in a 5% CO\u003csub\u003e2\u003c/sub\u003e atmosphere, cells on the upper side of the membrane were removed, and the membrane was fixed in 100% methanol for 10 min. Migrated cells on the lower surface were stained with 1% crystal violet (Sigma-Aldrich, St. Louis, MO, USA) and counted under a light microscope (100\u0026times; magnification, three random fields per well).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eEstablishment of ADAMTS1 overexpression of indicated cancer cells\u003c/h2\u003e\u003cp\u003eThe pLEX-MCS-ADAMTS1 expression construct was generously provided by Dr. T.C. Kuo (National Taiwan University, Taipei, Taiwan). To achieve ADAMTS1 overexpression, lentiviral particles carrying the pLEX-MCS-ADAMTS1 construct were produced and used to infect cells for 24 h, following a protocol described in our previous study [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eWound-healing assay\u003c/h2\u003e\u003cp\u003eCaki-1 cells with manipulated ADAMTS1 expression (2 \u0026times; 10⁵ cells/well) were seeded in 24-well plates and cultured for 24 h. A wound was then created by scratching the cell monolayer with a pipette tip. Cells were subsequently incubated in complete medium for another 24 h, and wound edges were photographed using a phase-contrast microscope at 100\u0026times; magnification.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eData collection from bioinformatics analyses\u003c/h2\u003e\u003cp\u003eRNA sequencing data for ccRCC (KIRC; \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;535) and HNSCC (HNSC; \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;519) were obtained from The Cancer Genome Atlas (TCGA) dataset via the UCSC Xena platform. A focal adhesion signature score was calculated using a single-sample gene set enrichment analysis (ssGSEA). The gene set for the focal adhesion pathway was derived from the Gene Ontology (GO) database. A Spearman correlation analysis was performed to assess the relationship between the focal adhesion signature and \u003cem\u003eADAMTS1\u003c/em\u003e gene expression.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eCell-adhesion assay\u003c/h2\u003e\u003cp\u003eADAMTS1 was either stably knocked down in RCC and OSCC cells, or cells were treated with various concentrations of tricin for 24 h. Cells were then resuspended at a density of 2 \u0026times; 10⁵ cells/mL in serum-containing medium and seeded into six-well plates. After a 1.5-h incubation period, nonadherent cells were removed by two rounds of gentle phosphate-buffered saline (PBS) washing. Adherent cells were subsequently fixed and stained with either 0.4% crystal violet or sulforhodamine (Sigma-Aldrich) for 15 min. After extensive rinsing, the dye was extracted using 30% acetic acid or 10 mM Tris base, and the absorbance was measured at 590 or 570 nm on a microplate reader (SpectraMax M2; Molecular Devices, Sunnyvale, CA, USA).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eData are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Statistical analyses were conducted using SPSS vers. 20 (SPSS, Chicago, IL, USA), and quantitative data were processed with GraphPad Prism 7 (GraphPad Software, San Diego, CA, USA). Differences between two groups were assessed using a two-tailed Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eBinding affinity analysis\u003c/h2\u003e\u003cp\u003eMolecular docking analysis of 26 compounds revealed tricin, dichotomitin, belamcandin, wogonin, and feralolide as the top five ligands with the most robust interactions with the active site of ADAMTS1 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among them, tricin showed the highest binding affinity with a score of \u0026minus;\u0026thinsp;10.93 kcal/mol. It formed hydrogen bonds with SER183 and GLU150, a π-interaction with HIS149, and metal coordination with ZN401. Dichotomitin exhibited the second strongest binding (\u0026minus;\u0026thinsp;8.235 kcal/mol), interacting with HIS176 and GLU150, forming a π-interaction with HIS149, and coordinating with ZN401. Belamcandin and wogonin respectively showed similar binding energies of \u0026minus;\u0026thinsp;8.159 and \u0026minus;\u0026thinsp;8.131 kcal/mol. Belamcandin formed hydrogen bonds with PHE145 and THR146, while wogonin interacted with GLU150. Feralolide, with a binding energy of \u0026minus;\u0026thinsp;8.04 kcal/mol, formed bonds with HIS176 and GLU150 and coordinated with ZN401 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\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\u003eBinding affinities of ligands from the molecular docking analysis\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\u003eSl. no.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLigands\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBinding affinity (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\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eBelamcandin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e-8.159\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDaidzein\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-6.682\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDehydrotanshinone II A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-5.411\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eDichotomitin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e-8.235\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDihydrosanguinarine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-6.311\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDuartin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-8.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eFeralolide\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e-8.04\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFlemiphilippinin C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.859\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFormononetin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlycyrol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-5.492\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLicochalcone a\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.274\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLupiwighteone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLyoniresinol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-5.727\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMatsukaze lactone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-5.379\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMenisporphine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-6.927\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMucronulatol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.983\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNoririsflorentin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.462\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNorwogonin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.938\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhaseolin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-5.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhaseollidin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-5.573\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRhamnazin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.844\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRhamnocitrin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.137\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSchisandrin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-3.382\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTricin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e-10.93\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVestitone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7.033\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eWogonin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e-8.131\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eBold font indicates the top five ligands with the strongest interactions at the ADAMTS1 active site.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\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\u003eTop 5 ligands with binding affinities and amino acid interactions\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=\"char\" char=\".\" 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\"\u003e\u003cp\u003eCompound Name\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAmino Acid residues\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDistance (\u0026deg;)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eType of Intreaction\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDocking Score (kcal/mol)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"13\" rowspan=\"14\"\u003e\u003cp\u003e\u003cb\u003eQFG\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTHR114\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.41872\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"13\" rowspan=\"14\"\u003e\u003cp\u003e-8.677\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.86962\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSER180\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.5477\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLY119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.58187\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eZN401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.23124\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMetal-Acceptor\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eZN401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.14407\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMetal-Acceptor\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eASP116\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.38927\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHalogen (Fluorine)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLN113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.81507\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Donor Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.88554\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Sigma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eALA179\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.58141\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU185\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.32508\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHE145\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.6581\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHE274\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.32333\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU185\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.20093\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"15\" rowspan=\"16\"\u003e\u003cp\u003e\u003cb\u003eTricin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eZN401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.02765\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAttractive Charge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"15\" rowspan=\"16\"\u003e\u003cp\u003e-10.93\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSER183\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.11342\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLU150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.8912\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSER183\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.97624\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTHR146\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.42323\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS159\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.76302\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS176\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.53743\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.83175\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Pi Stacked\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.5382\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Pi Stacked\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eALA179\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.3913\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU185\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.35449\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHE145\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.07508\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHE274\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.18681\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.23801\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eALA179\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.69816\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.16305\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"13\" rowspan=\"14\"\u003e\u003cp\u003e\u003cb\u003eDichotomitin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLU150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.52109\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"13\" rowspan=\"14\"\u003e\u003cp\u003e-8.235\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS176\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.80349\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTHR146\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.72301\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLN142\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.33478\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSER183\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.47781\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eZN401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.56856\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Cation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.85191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Pi Stacked\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.86144\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Pi Stacked\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.08461\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHE145\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.30532\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.78871\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHE274\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.44197\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.23368\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.08041\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"17\" rowspan=\"18\"\u003e\u003cp\u003e\u003cb\u003eBelamcandin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTHR146\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.09688\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"17\" rowspan=\"18\"\u003e\u003cp\u003e-8.159\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePRO275\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.74199\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSER183\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLU150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.77129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSER183\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.42795\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.44176\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Sigma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.77412\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Pi Stacked\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHE145\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.79578\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Pi T-shaped\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.87969\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePRO275\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.10733\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePRO275\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.93077\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHE145\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.9264\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.0166\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.47592\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS187\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.66042\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHE274\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.95244\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.72414\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU185\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.50287\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e\u003cb\u003eWogonin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLY119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.93215\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e-8.131\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLU150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.65143\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTHR146\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.45227\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMET181\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.68867\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eZN401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.95048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Cation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.82946\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Sigma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.94882\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Pi Stacked\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMET181\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.18898\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.92455\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.28565\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.43079\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eALA179\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.0156\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003e\u003cb\u003eFeralolide\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eZN401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.04044\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAttractive Charge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003e-8.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLY119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.97439\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLU150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.62508\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHIS176\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.19744\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConventional Hydrogen Bond\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLEU182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.60918\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Sigma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eALA179\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.08992\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi-Alkyl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eQFG, quantitative functional group.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFor docking validation, we checked key amino acids required for protein inhibition and compared them with interactions of the co-crystallized ligand, QFG. The 2D and 3D interaction diagrams for the top five ligands, compared with QFG, are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Comparative analysis of amino acid residues shows that QFG interacts with a unique and partially overlapping set of residues when compared with other candidate compounds. QFG notably binds with THR114, LEU118, SER180, GLY119, ASP116, GLN113, LEU182, ALA179, LEU185, PHE145, and PHE274, indicating a diverse range of interactions. Among these, LEU182, LEU185, ALA179, PHE145, and PHE274 are shared with multiple other candidates such as tricin, dichotomitin, belamcandin, and wogonin, suggesting these residues may represent key binding sites. The residue ZN401 appears frequently across QFG, tricin, wogonin, and feralolide, pointing to a common metal-binding interaction. However, QFG also exhibits unique contacts such as THR114, SER180, ASP116, and GLN113, which are not observed in the other compounds, potentially contributing to a distinct binding mode. In contrast, other candidates like tricin and belamcandin show extensive interactions with HIS149 and SER183, which are absent in QFG, indicating differences in their binding preferences (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA-L and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). We further superposed all docked ligands with QFGs. This helped visualize the alignment and assess how closely the new ligands mimicked the original binding mode (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eM). These results indicated strong and stable protein-ligand interactions, with tricin emerging as the most promising candidate.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eMolecular properties of selected ligands\u003c/h2\u003e\u003cp\u003eFurther, all candidate ligands were evaluated for their drug-likeness, key physicochemical parameters including MW, hydrogen bond donors and acceptors, Log P, TPSA, and Lipinski\u0026rsquo;s rule violations. The MWs of compounds ranged from 254.242 g/mol (daidzein) to 624.551 g/mol (isorhamnetin-3-O-β-D-rutinoside). Based on the highest binding affinity, tricin met the essential drug-likeness criteria. It has a molecular weight of 330.293 g/mol, which falls well within the acceptable range for oral drugs, and it possesses only five rotatable bonds, indicating good molecular rigidity. Tricin also has two hydrogen bond donors and 5.25 hydrogen bond acceptors, suggesting a good balance for forming specific interactions without compromising permeability. The log P value of 1.919 reflects moderate lipophilicity, which supports both membrane permeability and aqueous solubility. Its TPSA is 114.167 \u0026Aring;\u003csup\u003e2\u003c/sup\u003e, which is within the acceptable range for oral bioavailability. Importantly, tricin did not violate any of Lipinski\u0026rsquo;s rules, further confirming its suitability as a drug-like molecule (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\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\u003eEvaluation of drug-likeness of molecules based on Lipinski\u0026rsquo;s rule of five\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=\"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=\"left\" 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\u003eSr. no.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMolecule\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRotatable bonds\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMolecular weight\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eH-bond donors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eH-bond acceptors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLog P\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTPSA (\u0026Aring;2)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eViolation\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\u003e1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eAmurensin_qt\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e534.516\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e213.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eBelamcandin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e358.347\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3.438\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e83.431\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eDaidzein\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e254.242\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.814\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e80.486\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eDehydrotanshinone II A\u003c/b\u003e\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\u003e292.334\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.807\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e61.443\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eDichotomitin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e358.304\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.273\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e109.332\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eDihydrosanguinarine\u003c/b\u003e\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\u003e333.343\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3.615\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e40.483\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eDuartin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e332.352\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3.252\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e69.078\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eE-6-O-p-methoxycinnamoyl scandoside meth\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e564.542\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e18.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e-0.248\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e204.967\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eFeralolide\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e344.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.356\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e145.898\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eFlemiphilippinin C\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e434.488\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e5.452\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e87.042\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eFormononetin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e268.268\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.644\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e66.244\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eGlycyrol\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e366.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3.037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e96.795\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e13\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eIsoquercetin (2)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e464.382\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e-1.463\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e219.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eIsorhamnetin-3-o-beta-d-rutinoside\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e624.551\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e-1.867\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e258.173\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eLicochalcone a\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e338.402\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e74.376\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eLupiwighteone\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e338.359\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3.416\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e95.192\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e17\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eLyoniresinol\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e420.458\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e113.209\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e18\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMatsukaze lactone\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e350.327\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.457\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e94.587\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e19\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMenisporphine\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e321.332\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3.023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e57.788\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMucronulatol\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e302.326\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.998\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e66.789\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eNoririsflorentin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e372.331\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.774\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e95.637\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eNorwogonin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e270.241\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.763\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e97.582\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e23\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003ePhaseolin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e322.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e4.227\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e46.252\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e24\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003ePhaseollidin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e324.376\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e59.962\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e25\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eRhamnazin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e330.293\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.051\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e114.286\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e26\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eRhamnocitrin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e300.267\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.914\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e106.873\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e27\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eSchisandrin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e432.513\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e5.186\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e57.062\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e28\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTricin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e330.293\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.919\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e114.167\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e29\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eVestitone\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e286.284\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.932\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e85.794\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e30\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eWogonin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e284.268\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.451\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e83.191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eTPSA, topological polar surface area.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003ePK property predictions using SwissADME\u003c/h2\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the water solubility, PKs, and drug-likeness profiles of five compounds\u0026mdash;tricin, dichotomitin, belamcandin, wogonin, and feralolide\u0026mdash;were analyzed. Solubility data, predicted using ESOL (estimated solubility) and Ali models, classified most of the compounds as moderately soluble, with minor variations. Tricin exhibited an ESOL solubility of 0.0252 mg/ml and 0.00306 mg/ml in the Ali model, while dichotomitin showed slightly higher solubilities of 0.0305 (ESOL) and 0.00723 mg/ml (Ali). Belamcandin and wogonin maintained moderate solubilities across both models, although belamcandin was classified as poorly soluble in the Silicos-IT model. Feralolide displayed the lowest solubility in the Ali model (0.00114 mg/ml) but was deemed soluble by Silicos-IT.\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\u003ePharmacokinetic properties of the top five ligands\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"25\"\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\u003cdiv align=\"left\" 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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c17\" colnum=\"17\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c18\" colnum=\"18\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c19\" colnum=\"19\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c20\" colnum=\"20\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c21\" colnum=\"21\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c22\" colnum=\"22\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c23\" colnum=\"23\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c24\" colnum=\"24\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c25\" colnum=\"25\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMolecule\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"24\" nameend=\"c25\" namest=\"c2\"\u003e\u003cp\u003eWater solubility\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eESOL Log S\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003eESOL solubility (mg/ml)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003eESOL solubility (mol/l)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e\u003cp\u003eESOL class\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c14\" namest=\"c12\"\u003e\u003cp\u003eAli Log S\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c17\" namest=\"c15\"\u003e\u003cp\u003eAli solubility (mg/ml)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003eAli solubility (mol/l)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c23\" namest=\"c20\"\u003e\u003cp\u003eAli class\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c25\" namest=\"c24\"\u003e\u003cp\u003eSilicos-IT 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\u003eTricin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-4.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e2.52E-02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e7.63E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c14\" namest=\"c12\"\u003e\u003cp\u003e-5.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c17\" namest=\"c15\"\u003e\u003cp\u003e3.06E-03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e9.26E-06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c23\" namest=\"c20\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c25\" namest=\"c24\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDichotomitin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-4.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e3.05E-02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e8.51E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c14\" namest=\"c12\"\u003e\u003cp\u003e-4.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c17\" namest=\"c15\"\u003e\u003cp\u003e7.23E-03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e2.02E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c23\" namest=\"c20\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c25\" namest=\"c24\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBelamcandin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-4.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e2.06E-02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e5.74E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c14\" namest=\"c12\"\u003e\u003cp\u003e-4.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c17\" namest=\"c15\"\u003e\u003cp\u003e6.10E-03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e1.70E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c23\" namest=\"c20\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c25\" namest=\"c24\"\u003e\u003cp\u003ePoorly soluble\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWogonin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-4.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e1.66E-02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e5.85E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c14\" namest=\"c12\"\u003e\u003cp\u003e-4.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c17\" namest=\"c15\"\u003e\u003cp\u003e4.01E-03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e1.41E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c23\" namest=\"c20\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c25\" namest=\"c24\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFeralolide\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-4.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e2.45E-02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e7.11E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c14\" namest=\"c12\"\u003e\u003cp\u003e-5.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c17\" namest=\"c15\"\u003e\u003cp\u003e1.14E-03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e3.30E-06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c23\" namest=\"c20\"\u003e\u003cp\u003eModerately soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c25\" namest=\"c24\"\u003e\u003cp\u003eSoluble\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eMolecule\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"24\" nameend=\"c25\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003ePharmacokinetics\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eHuman intestinal absorption\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003e\u003cb\u003eBBB permeant\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003e\u003cb\u003ePgp substrate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c13\" namest=\"c11\"\u003e\u003cp\u003e\u003cb\u003eCYP1A2 inhibitor\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e\u003cb\u003eCYP2C19 inhibitor\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c18\" namest=\"c17\"\u003e\u003cp\u003e\u003cb\u003eCYP2C9 inhibitor\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c21\" namest=\"c19\"\u003e\u003cp\u003e\u003cb\u003eCYP2D6 inhibitor\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c24\" namest=\"c22\"\u003e\u003cp\u003e\u003cb\u003eCYP3A4 inhibitor\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003elog Kp (cm/s)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTricin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c13\" namest=\"c11\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c18\" namest=\"c17\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c21\" namest=\"c19\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c24\" namest=\"c22\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e-6.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDichotomitin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c13\" namest=\"c11\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c18\" namest=\"c17\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c21\" namest=\"c19\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c24\" namest=\"c22\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e-6.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBelamcandin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c13\" namest=\"c11\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c18\" namest=\"c17\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c21\" namest=\"c19\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c24\" namest=\"c22\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e-6.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWogonin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c13\" namest=\"c11\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c18\" namest=\"c17\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c21\" namest=\"c19\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c24\" namest=\"c22\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e-5.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFeralolide\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c13\" namest=\"c11\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c18\" namest=\"c17\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c21\" namest=\"c19\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c24\" namest=\"c22\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e-6.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eMolecule\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"17\" nameend=\"c18\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eDrug likeness\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c25\" namest=\"c19\"\u003e\u003cp\u003e\u003cb\u003eMedicinal chemistry\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eLipinski #violations\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003e\u003cb\u003eGhose #violations\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003e\u003cb\u003eVeber #violations\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e\u003cp\u003e\u003cb\u003eEgan #violations\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c15\" namest=\"c13\"\u003e\u003cp\u003e\u003cb\u003eMuegge #violations\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c18\" namest=\"c16\"\u003e\u003cp\u003e\u003cb\u003eBioavailability score\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c20\" namest=\"c19\"\u003e\u003cp\u003e\u003cb\u003ePAINS #alerts\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c22\" namest=\"c21\"\u003e\u003cp\u003e\u003cb\u003eBrenk #alerts\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c25\" namest=\"c23\"\u003e\u003cp\u003e\u003cb\u003eLead likeness #violations\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTricin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c15\" namest=\"c13\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c18\" namest=\"c16\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c20\" namest=\"c19\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c22\" namest=\"c21\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c25\" namest=\"c23\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDichotomitin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c15\" namest=\"c13\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c18\" namest=\"c16\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c20\" namest=\"c19\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c22\" namest=\"c21\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c25\" namest=\"c23\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBelamcandin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c15\" namest=\"c13\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c18\" namest=\"c16\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c20\" namest=\"c19\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c22\" namest=\"c21\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c25\" namest=\"c23\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWogonin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c15\" namest=\"c13\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c18\" namest=\"c16\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c20\" namest=\"c19\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c22\" namest=\"c21\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c25\" namest=\"c23\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFeralolide\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c15\" namest=\"c13\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c18\" namest=\"c16\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c20\" namest=\"c19\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c22\" namest=\"c21\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c25\" namest=\"c23\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"25\"\u003eESOL, estimated solubility; PAINS, Pan-Assay Interference Compounds; BBB, blood-brain barrier; Pgp, P-glycoprotein.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003ePK profiling revealed high GI absorption for all compounds, but none was capable of penetrating the BBB or acting as a Pgp substrate. With the exception of feralolide, which showed no inhibitory action on cytochrome P450 enzymes, the remaining four compounds consistently inhibited CYP1A2, CYP2C9, CYP2D6, and CYP3A4. Skin permeability (log Kp) values ranged from \u0026minus;\u0026thinsp;6.51 to -5.56, indicating low dermal absorption. The drug-likeness evaluation confirmed compliance with the Lipinski, Ghose, Veber, Egan, and Muegge rules for all compounds, with no violations detected. The bioavailability score was uniform (0.55) for all five, indicating moderate bioavailability. There were no PAINS or Brenk alerts, suggesting a low risk of promiscuous reactivity. However, dichotomitin and belamcandin had a single lead-likeness violation each, highlighting potential challenges in optimization for lead development. Collectively, these results established a clear understanding of the physicochemical, PKs, and drug-likeness characteristics of the studied compounds.\u003c/p\u003e\u003cp\u003eAmong the five compounds analyzed, tricin demonstrated the most favorable overall profile based on water solubility, PKs, and drug-likeness characteristics. In terms of solubility, while tricin was classified as moderately soluble by both the ESOL and Ali models (0.0252 and 0.00306 mg/ml, respectively), it maintained a consistent moderate solubility rating across all three predictive models (ESOL, Ali, and Silicos-IT), avoiding the poor solubility classification seen for belamcandin. Despite being a non-BBB permeant and non-Pgp substrate, its balanced enzyme inhibition profile suggested a promising pharmacological spectrum. Furthermore, tricin excelled in the drug-likeness and medicinal chemistry evaluations with zero violations of the Lipinski, Ghose, Veber, Egan, and Muegge criteria, indicating strong compliance with drug-like properties. It also maintained a moderate bioavailability score of 0.55, with no PAINS, Brenk, or lead-likeness violations, ensuring high chemical stability and reduced risk of non-specific interactions.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAt a non-toxic concentration, tricin exerted significant anti-migration effects by targeting ADAMTS1 in OSCC and RCC cells\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe further investigated whether tricin, identified as the compound with the highest affinity for ADAMTS1, could inhibit its function in cancer. Our previous studies demonstrated that ADAMTS1 promotes OSCC tumor metastasis, with EGFR identified as a key downstream target involved in its pro-metastatic activity [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A Western blot analysis revealed that OSCC cell lines, including HSC-3, HSC-3M, and SAS, expressed relatively higher levels of ADAMTS1 compared to SCC9 cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Notably, tricin treatment at 6.25 and 12.5 \u0026micro;M resulted in marked downregulation of ADAMTS1 and EGFR in HSC-3M and SAS cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), suggesting that tricin broadly suppresses the ADAMTS1-EGFR signaling axis in OSCC cells. Functionally, significant anti-migratory effects of tricin at 6.25 and 12.5 \u0026micro;M after 24 h of treatment were observed in SAS and HSC-3M cells, but not in SCC9 cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), suggesting that tricin selectively inhibits migration in OSCC cells with high ADAMTS1 expression. Furthermore, ADAMTS1 overexpression significantly reversed the migration inhibition caused by tricin treatment in HSC-3 cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). To rule out the possibility that the reduced number of migrating cells was due to decreased cell viability, we performed a CCK-8 assay on SAS and HSC-3M cells treated with the same concentrations of tricin for an extended period (72 h). Both 6.25 and 12.5 \u0026micro;M tricin showed minimal cytotoxicity in SAS cells, with no significant effect on HSC-3M cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). Collectively, these results suggest that tricin, at non-cytotoxic concentrations, impairs the motility of OSCC cells by targeting ADAMTS1.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn addition to OSCC, the oncogenic role of the ADAMTS1-EGFR axis was also validated in RCC [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. A Western blot analysis from our previous study indicated that RCC cell lines, including Caki-1, 786-O, and Achn, expressed relatively higher levels of ADAMTS1 compared to A498 cells [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Tricin treatment predominantly inhibited expression of the ADAMTS1-EGFR axis in both Caki-1 and 786-O cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Moreover, a significant anti-migratory effect of tricin was observed in RCC cells (786-O and Caki-1) with high ADAMTS1 expression, but not in A498 cells, which expressed very low levels of ADAMTS1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Additionally, only 12.5 \u0026micro;M tricin exhibited minimal cytotoxicity in 786-O cells, with no significant effect observed in Caki-1 cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Similar to the findings in OSCC, non-toxic concentrations of tricin were also able to suppress the motility of RCC cells by targeting ADAMTS1.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eAt a non-toxic concentration, tricin exerts significant anti-adhesive effects by targeting ADAMTS1 in OSCC and RCC cells\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn addition to cell motility, the adhesive ability of cancer cells is also critical for metastasis [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. ADAMTS1 was reported to enhance the adhesive capacity of breast cancer cells [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In this study, manipulation of ADAMTS1 expression affected the migratory capacity of SAS, HSC-3M, and 786-O cells in a transwell migration assay (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA), but had no effect on wound closure in a wound-healing assay (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB), suggesting that adhesion may be a key mechanism through which ADAMTS1 influences cancer cell motility. Clinically, a strong correlation was observed between ADAMTS1 expression and a focal adhesion-related gene signature in human ccRCC and HNSCC samples obtained from TCGA database (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). Notably, knockdown of ADAMTS1 significantly reduced the adhesive abilities of various RCC (Caki-1 and 786-O) and OSCC (SAS and HSC-3M) cell lines (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD). Furthermore, treatment of RCC and OSCC cells with different concentrations of tricin markedly attenuated their adhesive properties (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE, right panel). With increasing tricin concentrations, OSCC and RCC cells that exhibited a spread, adhesive morphology (indicated by red arrows) transitioned to a more-rounded, less-adhesive phenotype (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE, left panel). In contrast, the inhibitory effect of tricin on cell adhesion was not observed in A498 cells, which express very low levels of ADAMTS1 (Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Overexpression of ADAMTS1 in HSC-3 cells significantly reversed the tricin-induced inhibition of adhesion (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eF), suggesting that tricin selectively inhibits the adhesive ability of cancer cells with high ADAMTS1 expression. FAK and Src, two tyrosine kinases that are part of the focal adhesion-related gene signature described above, play critical roles in cell adhesion and migration, particularly in the context of cancer [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In this study, we found that tricin treatment also suppressed activation of FAK and Src in HSC-3M and Caki-1 cells, as indicated by downregulation of p-FAK (Tyr397) and p-Src (Tyr416) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eG).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eResults of our research provide encouraging evidence supporting ADAMTS1 inhibitors as potential drug candidates for cancer treatment. Through molecular docking and ADMET predictions, we identified several small molecules\u0026mdash;particularly tricin\u0026mdash;that exhibited potential inhibitory activity against ADAMTS1, a key player in cancer progression [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Tricin\u0026rsquo;s binding to ADAMTS1 with the strongest binding affinity of \u0026minus;\u0026thinsp;10.93 kcal/mol suggests that it could be a highly effective inhibitor, altering the protein structure and blocking its activity in ECM remodeling, which is essential for tumor metastasis. Our previous studies demonstrated that the ADAMTS1-EGFR axis is critical for promoting several steps in tumor metastasis, including motility and resistance to anoikis in OSCC and RCC [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In vivo, we found that ADAMTS1 overexpression significantly promoted tumor metastasis of RCC and OSCC in zebrafish xenograft and mouse orthotopic xenograft models [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In the present study, our in vitro assays demonstrated that tricin treatment suppressed expression of the ADAMTS1-EGFR axis in OSCC and RCC cells. Tricin effectively inhibited the migratory and adhesive capacities of both cancer types, particularly in cell lines with high ADAMTS1 expression. FAK and Src are critical regulators of cancer cell adhesion and migration, and EGFR/Src signaling was reported to activate FAK in cancers [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. We observed that tricin also inhibited activation of both Src and FAK in OSCC and RCC cells, suggesting that this effect may result from tricin-induced suppression of the ADAMTS1-EGFR axis. Moreover, our previous study demonstrated that apigenin functions as a potential inhibitor of the ADAMTS1-EGFR axis and effectively suppresses ADAMTS1-induced enhancement of in vitro invasion and in vivo lymph node metastasis in OSCC [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Apigenin and tricin, flavones respectively found in leafy vegetables and rice bran, share similar structures: tricin (4\u0026rsquo;,5,7-trihydroxy-3\u0026rsquo;,5\u0026rsquo;-dimethoxyflavone) is closely related to apigenin (4\u0026rsquo;,5,7-trihydroxyflavone). A previous study reported that when administered to mice through the diet, tricin levels in plasma, the liver, and mucosa exceeded those of apigenin by 350%, 33%, and 100%, respectively. These findings suggest that tricin has greater in vivo bioavailability compared to apigenin [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Therefore, tricin may possess a PK advantage over apigenin, suggesting it may exhibit a more-potent anti-metastatic effect in OSCC and RCC. Taken together, these findings suggest that tricin may serve as a potential anti-metastatic agent in specific cancer types characterized by high ADAMTS1 expression.\u003c/p\u003e\u003cp\u003eThe active site region of ADAMTS1, characterized by the catalytic zinc-binding motif (ZN 401) and surrounding residues (Thr117, Leu118, Ile120, His149, His153, His159, and Met177), was described in structural and functional studies of ADAMTS family proteins [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The molecular docking analysis showed that tricin had a higher binding score than other potential screened compounds, such as dichotomitin, belamcandin, and wogonin. The observed metal coordination with tricin supports the role of the catalytic zinc ion (Zn\u0026sup2;⁺) in stabilizing ligand binding, a characteristic feature of ADAMTS metalloproteinases. These findings reinforce the specificity of binding within the active site and highlight the therapeutic potential of these small molecules as ADAMTS1 inhibitors. These highlight their potential as promising candidates for future cancer therapies.\u003c/p\u003e\u003cp\u003eSwissADME PK profiling also confirmed the drug-likeness of tricin, dichotomitin, belamcandin, wogonin, and feralolide. All compounds passed major filters such as the Lipinski, Ghose, Veber, Egan, and Muegge rules without any violations and showed a consistent bioavailability score of 0.55. Furthermore, no PAINS or Brenk alerts were detected, indicating a low risk of toxicity or reactivity. Only dichotomitin and belamcandin exhibited one lead-likeness violation each, which may limit their use in early drug discovery. In terms of PKs, all compounds showed high human HIA, suggesting that they are potentially orally bioavailable. Predictions of other ADMET properties for these candidate compounds also revealed favorable PK profiles, further supporting their potential for development as drug candidates. These findings highlight the therapeutic promise of natural and synthetic inhibitors of ADAMTS1 for cancer treatment. However, despite computational studies providing valuable data, experimental confirmation with in vivo models is required to determine the effectiveness and safety of these molecules. Further studies are also needed to explore the specific mechanisms by which these inhibitors control ADAMTS1 expression and influence the overall TME, particularly in relation to metastasis.\u003c/p\u003e\u003cp\u003eIn this study, a comprehensive computational approach was used to identify and evaluate potential inhibitors of ADAMTS1, an important enzyme involved in cancer progression. Molecular docking results recognized tricin as the lead compound with optimal binding affinity along with favorable PK properties, making it an appropriate candidate for further preclinical development. Moreover, results from functional assays indicated the possibility of tricin being a candidate for cancer treatment in the future, particularly as more-effective treatments for ADAMTS1-enriched cancer types (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Lastly, our findings also revealed several other compounds with potential inhibitory effects on ADAMTS1, suggesting that ADAMTS1 inhibition by small-molecule inhibitors could be a novel therapeutic strategy for managing aggressive cancers.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eADAMTS1\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ea disintegrin and metalloproteinase with thrombospondin motifs 1\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eADMET\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eabsorption,distribution,metabolism,excretion,and toxicity\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOSCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eoral squamous cell carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eccRCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eclear cell renal cell carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEGFR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eepidermal growth factor receptor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFAK\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003efocal adhesion kinase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSMILES\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSimplified Molecular Input Line Entry System\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePAINS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePan-Assay Interference Compounds\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTCGA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eThe Cancer Genome Atlas\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003essGSEA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003esingle-sample gene set enrichment analysis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGene Ontology\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePK\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epharmacokinetic\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCYP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecytochrome P450\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCCK-8\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCell Counting Kit-8.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo author declared any conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAS, CHL, and MHC designed and conceived the study. MCT and MHC supervised the study. AS and SG contribute to the molecular docking and ADMET analysis. CHL, YWL, and YCW performed the \u003cem\u003ein vitro\u003c/em\u003e experiments and acquired the data. YCY, WJL, and MHC contributed to the bioinformatic analysis\u0026nbsp;and statistical analyses.\u0026nbsp;MHC and MCT\u0026nbsp;wrote and revised the manuscript. All authors reviewed the results and\u0026nbsp;agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Research Center of Cancer Translational Medicine at Taipei Medical University, under the Featured Areas Research Center Program of the Higher Education Sprout Project, Ministry of Education, Taiwan (awarded to M.-H.C.). Additional support was provided by Wan Fang Hospital, Taipei Medical University (grant no. 113TMU-WFH-01, awarded to Y.-C.W.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data supporting the findings of this study are included in the article. Original datasets are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWang, Z., et al., \u003cem\u003eRole of ADAM and ADAMTS proteases in pathological tissue remodeling.\u003c/em\u003e Cell Death Discov, 2023. \u003cstrong\u003e9\u003c/strong\u003e(1): p. 447.\u003c/li\u003e\n\u003cli\u003eBacchetti, R., S. Yuan, and E. Rainero, \u003cem\u003eADAMTS Proteases: Their Multifaceted Role in the Regulation of Cancer Metastasis.\u003c/em\u003e Dis Res, 2024. \u003cstrong\u003e4\u003c/strong\u003e(1): p. 40-52.\u003c/li\u003e\n\u003cli\u003eSzmajda-Krygier, D., et al., \u003cem\u003eAssessment of Methylation in Selected ADAMTS Family Genes in Non-Small-Cell Lung Cancer.\u003c/em\u003e Int J Mol Sci, 2025. \u003cstrong\u003e26\u003c/strong\u003e(3).\u003c/li\u003e\n\u003cli\u003eCal, S. and C. L\u0026oacute;pez-Ot\u0026iacute;n, \u003cem\u003eADAMTS proteases and cancer.\u003c/em\u003e Matrix Biol, 2015. \u003cstrong\u003e44-46\u003c/strong\u003e: p. 77-85.\u003c/li\u003e\n\u003cli\u003eKumar, S., N. Rao, and R. Ge, \u003cem\u003eEmerging Roles of ADAMTSs in Angiogenesis and Cancer.\u003c/em\u003e Cancers (Basel), 2012. \u003cstrong\u003e4\u003c/strong\u003e(4): p. 1252-99.\u003c/li\u003e\n\u003cli\u003eHu, X., et al., \u003cem\u003eADAMTS1 induces epithelial-mesenchymal transition pathway in non-small cell lung cancer by regulating TGF-\u0026beta;.\u003c/em\u003e Aging (Albany NY), 2023. \u003cstrong\u003e15\u003c/strong\u003e(6): p. 2097-2114.\u003c/li\u003e\n\u003cli\u003eRocks, N., et al., \u003cem\u003eADAMTS-1 metalloproteinase promotes tumor development through the induction of a stromal reaction in vivo.\u003c/em\u003e Cancer Res, 2008. \u003cstrong\u003e68\u003c/strong\u003e(22): p. 9541-50.\u003c/li\u003e\n\u003cli\u003eRedondo-Garc\u0026iacute;a, S., et al., \u003cem\u003eADAMTS proteases and the tumor immune microenvironment: Lessons from substrates and pathologies.\u003c/em\u003e Matrix Biol Plus, 2021. \u003cstrong\u003e9\u003c/strong\u003e: p. 100054.\u003c/li\u003e\n\u003cli\u003eChien, M.H., et al., \u003cem\u003eCyclic increase in the ADAMTS1-L1CAM-EGFR axis promotes the EMT and cervical lymph node metastasis of oral squamous cell carcinoma.\u003c/em\u003e Cell Death Dis, 2024. \u003cstrong\u003e15\u003c/strong\u003e(1): p. 82.\u003c/li\u003e\n\u003cli\u003eWen, Y.C., et al., \u003cem\u003eThe oncogenic ADAMTS1-VCAN-EGFR cyclic axis drives anoikis resistance and invasion in renal cell carcinoma.\u003c/em\u003e Cell Mol Biol Lett, 2024. \u003cstrong\u003e29\u003c/strong\u003e(1): p. 126.\u003c/li\u003e\n\u003cli\u003eTan Ide, A., C. Ricciardelli, and D.L. Russell, \u003cem\u003eThe metalloproteinase ADAMTS1: a comprehensive review of its role in tumorigenic and metastatic pathways.\u003c/em\u003e Int J Cancer, 2013. \u003cstrong\u003e133\u003c/strong\u003e(10): p. 2263-76.\u003c/li\u003e\n\u003cli\u003eKhan, S.U., K. Fatima, and F. Malik, \u003cem\u003eUnderstanding the cell survival mechanism of anoikis-resistant cancer cells during different steps of metastasis.\u003c/em\u003e Clin Exp Metastasis, 2022. \u003cstrong\u003e39\u003c/strong\u003e(5): p. 715-726.\u003c/li\u003e\n\u003cli\u003eDavies, C.R., et al., \u003cem\u003eThe potential of using circulating tumour cells and their gene expression to predict docetaxel response in metastatic prostate cancer.\u003c/em\u003e Front Oncol, 2022. \u003cstrong\u003e12\u003c/strong\u003e: p. 1060864.\u003c/li\u003e\n\u003cli\u003eWang, S., et al., \u003cem\u003eADAMTS1 as potential prognostic biomarker promotes malignant invasion of glioma.\u003c/em\u003e Int J Clin Oncol, 2023. \u003cstrong\u003e28\u003c/strong\u003e(1): p. 52-68.\u003c/li\u003e\n\u003cli\u003eHirano, T., et al., \u003cem\u003eInhibition of tumor growth by antibody to ADAMTS1 in mouse xenografts of breast cancer.\u003c/em\u003e Anticancer Res, 2011. \u003cstrong\u003e31\u003c/strong\u003e(11): p. 3839-42.\u003c/li\u003e\n\u003cli\u003ePluda, S., Y. Mazzocato, and A. Angelini, \u003cem\u003ePeptide-Based Inhibitors of ADAM and ADAMTS Metalloproteinases.\u003c/em\u003e Front Mol Biosci, 2021. \u003cstrong\u003e8\u003c/strong\u003e: p. 703715.\u003c/li\u003e\n\u003cli\u003eDaina, A., O. Michielin, and V. Zoete, \u003cem\u003eSwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules.\u003c/em\u003e Sci Rep, 2017. \u003cstrong\u003e7\u003c/strong\u003e: p. 42717.\u003c/li\u003e\n\u003cli\u003eMorris, G.M., et al., \u003cem\u003eAutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.\u003c/em\u003e J Comput Chem, 2009. \u003cstrong\u003e30\u003c/strong\u003e(16): p. 2785-91.\u003c/li\u003e\n\u003cli\u003eLi, H., et al., \u003cem\u003eImproving AutoDock Vina Using Random Forest: The Growing Accuracy of Binding Affinity Prediction by the Effective Exploitation of Larger Data Sets.\u003c/em\u003e Mol Inform, 2015. \u003cstrong\u003e34\u003c/strong\u003e(2-3): p. 115-26.\u003c/li\u003e\n\u003cli\u003eTrott, O. and A.J. Olson, \u003cem\u003eAutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.\u003c/em\u003e J Comput Chem, 2010. \u003cstrong\u003e31\u003c/strong\u003e(2): p. 455-61.\u003c/li\u003e\n\u003cli\u003eSakhawat, A., et al., \u003cem\u003eNatural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis.\u003c/em\u003e AMB Express, 2023. \u003cstrong\u003e13\u003c/strong\u003e(1): p. 134.\u003c/li\u003e\n\u003cli\u003eTseng, T.H., et al., \u003cem\u003eInhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21(WAF1/CIP1) expression.\u003c/em\u003e Environ Toxicol, 2017. \u003cstrong\u003e32\u003c/strong\u003e(2): p. 434-444.\u003c/li\u003e\n\u003cli\u003eChien, M.H., et al., \u003cem\u003eTargeting the SPOCK1-snail/slug axis-mediated epithelial-to-mesenchymal transition by apigenin contributes to repression of prostate cancer metastasis.\u003c/em\u003e J Exp Clin Cancer Res, 2019. \u003cstrong\u003e38\u003c/strong\u003e(1): p. 246.\u003c/li\u003e\n\u003cli\u003eLin, Y.W., et al., \u003cem\u003eStabilization of ADAM9 by N-\u0026alpha;-acetyltransferase 10 protein contributes to promoting progression of androgen-independent prostate cancer.\u003c/em\u003e Cell Death Dis, 2020. \u003cstrong\u003e11\u003c/strong\u003e(7): p. 591.\u003c/li\u003e\n\u003cli\u003eWen, Y.C., et al., \u003cem\u003eMelatonin-triggered post-transcriptional and post-translational modifications of ADAMTS1 coordinately retard tumorigenesis and metastasis of renal cell carcinoma.\u003c/em\u003e J Pineal Res, 2020. \u003cstrong\u003e69\u003c/strong\u003e(2): p. e12668.\u003c/li\u003e\n\u003cli\u003eYayan, J., et al., \u003cem\u003eAdhesion, metastasis, and inhibition of cancer cells: a comprehensive review.\u003c/em\u003e Mol Biol Rep, 2024. \u003cstrong\u003e51\u003c/strong\u003e(1): p. 165.\u003c/li\u003e\n\u003cli\u003eTan, I.A., et al., \u003cem\u003eADAMTS1 Promotes Adhesion to Extracellular Matrix Proteins and Predicts Prognosis in Early Stage Breast Cancer Patients.\u003c/em\u003e Cell Physiol Biochem, 2019. \u003cstrong\u003e52\u003c/strong\u003e(6): p. 1553-1568.\u003c/li\u003e\n\u003cli\u003eBol\u0026oacute;s, V., et al., \u003cem\u003eThe dual kinase complex FAK-Src as a promising therapeutic target in cancer.\u003c/em\u003e Onco Targets Ther, 2010. \u003cstrong\u003e3\u003c/strong\u003e: p. 83-97.\u003c/li\u003e\n\u003cli\u003eTai, Y.L., et al., \u003cem\u003eAn EGFR/Src-dependent \u0026beta;4 integrin/FAK complex contributes to malignancy of breast cancer.\u003c/em\u003e Sci Rep, 2015. \u003cstrong\u003e5\u003c/strong\u003e: p. 16408.\u003c/li\u003e\n\u003cli\u003eCai, H., et al., \u003cem\u003eTissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties.\u003c/em\u003e Cancer Chemother Pharmacol, 2007. \u003cstrong\u003e60\u003c/strong\u003e(2): p. 257-66.\u003c/li\u003e\n\u003cli\u003eDe Savi, C., et al., \u003cem\u003eThe design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis.\u003c/em\u003e Bioorg Med Chem Lett, 2011. \u003cstrong\u003e21\u003c/strong\u003e(5): p. 1376-81.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","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":"ADAMTS1, Molecular docking, Tricin, Metastasis, Renal cell carcinoma, Oral squamous cell carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-7521823/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7521823/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) plays a crucial role in extracellular matrix (ECM) remodeling, cancer metastasis, and regulation of the tumor microenvironment. As ADAMTS1 has been implicated in tumor-promoting mechanisms across various cancer types, its inhibition has shown potential as a therapeutic strategy for aggressive cancers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eIn this study, we employed molecular docking and pharmacokinetic profiling to identify potential small-molecule inhibitors of ADAMTS1. In total, 26 natural and synthetic compounds were screened against ADAMTS1 using AutoDock Vina, followed by absorption, distribution, metabolism, excretion, and toxicity (ADMET)predictions via SwissADME. The \u003cem\u003ein vitro\u003c/em\u003emigratory ability of cancer cells was assessed by transwell migration assay. Protein-based biochemical assays such as Western blotting to investigate ADAMTS1-regulated pathway.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eWe identified tricin as the lead compound (binding energy: –10.93 kcal/mol), a natural product with high oral absorption and non-carcinogenic properties. Functional assays revealed that tricin, at non-toxic concentrations, significantly inhibited the migratory and adhesive abilities of various oral squamous cell carcinoma (OSCC) and clear cell renal cell carcinoma (ccRCC) cell lines by suppressing expression or activation of ADAMTS1 and its downstream effectors including epidermal growth factor receptor (EGFR), Src, and focal adhesion kinase (FAK).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: These findings provide a computational framework for identifying tricin as a potential ADAMTS1 inhibitor and support its validation as a therapeutic agent for treating cancer metastasis, particularly in cancer types with high ADAMTS1 expression.\u003c/p\u003e","manuscriptTitle":"Discovery of tricin as a novel ADAMTS1 inhibitor via molecular docking and ADMET predictions for inhibiting cancer metastasis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-18 08:08:57","doi":"10.21203/rs.3.rs-7521823/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":"a79a9a74-7a9b-4081-a901-e70b3d80dbfc","owner":[],"postedDate":"September 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-02T05:04:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-18 08:08:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7521823","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7521823","identity":"rs-7521823","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}