Multitargeted antidiabetic intervention of phytocompounds of methanolic fruit extract of Cordia myxa L.: Integrated from in-silico and in-vivo studies

Multitargeted antidiabetic intervention of phytocompounds of methanolic fruit extract of Cordia myxa L.: Integrated from in-silico and in-vivo studies | 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 Multitargeted antidiabetic intervention of phytocompounds of methanolic fruit extract of Cordia myxa L.: Integrated from in-silico and in-vivo studies Chandra Kala, Kamlesh Kumar, Kirti Rathore, Kavita Kumari Gaur, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8824801/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract The current study aimed to investigate the multitargeted antidiabetic potential of the methanolic extract of C. myxa fruits (MECMF) through in-silico and in-vivo assessments. Chemical fingerprinting of the test extract was performed using LC–MS/MS, with authentication of the UNIFI scientific library database. Potent phytocompounds were screened out by using the protein ligand molecular docking against the multitargets (dipeptidyl peptidase-4 (DPP-4), α-amylase, and α-glycosidase) through assessments of binding energy and related parameters. Further validation of interactions with target proteins was examined by following the molecular dynamics simulations at 1ns with the standard conditions by calculations of RSMD, and hydrogen bond profiling. The assessments of molecular dynamic simulation showed significant interactions by the selected three complexes i.e ., DPP-4 -β-sitosterol, α-amylase-cordiaquinone C, and α-glycosidase-cordiaquinone G. ADMET revealed substantial drug likeness characteristics of the screened phytocompounds. Consequently, the nicotinamide–streptozotocin–induced type 2 diabetic rat model was utilized for biochemical and histological studies. The treatment of the test extract and standard drug (sitagliptin) showed alterations in HOMA indices, lipid metabolism, oxidative stress, and histology of the pancreas. Substantial improvements were revealed by the treatment of the test extract in the histoarchitectures of pancreases through reducing the degenerative changes. These kinds of alterations were followed by the ameliorated oxidative stress through significant improvements in the FRAP, GSH, and LPO. Collectively, it can be concluded that phytocompounds of the C. myxa have capabilities to interfere in glucose metabolism through a multitargeted approach. Further experimentation can be promoting the drug development practices for the therapeutics of diabetes. Cordia myxa L. medicinal plant antidiabetic phytochemicals DPP-4 antioxidant Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Introduction Conventional food recipes and formulations are selective collections of potent indigenous ingredient which capabilities to interfere in several metabolic pathways and are marked to be therapeutic potential. These ingredients often contain bioactive compounds such as polyphenols, flavonoids, and essential oils, which can be interacting with key enzymes and receptors of metabolism. Accordingly, the unripen fruit of Cordia myxa L. is a key component of the local food recipe of the panchkutta of western Rajasthan, which possesses numerous medicinal properties. Despite its significant nutritional and therapeutic properties, as well as its ability to grow in harsh climatic conditions, it has not gained widespread attention. Traditionally, various parts of the plant have been used in folk medicine to treat a wide range of ailments, including inflammatory conditions, liver diseases, respiratory issues, gastrointestinal disturbances, and metabolic disorders [ 1 – 3 ]. Phytochemical profiling of C. myxa fruits has identified a diverse array of bioactive compounds, including flavonoids, phenolic acids, sterols, terpenoids, saponins, and quinones, many of which have antioxidant, anti-inflammatory, and enzyme-modulating activities [ 4 , 5 ]. The abundance of these pharmacologically active compounds suggests that the plant may help regulate blood glucose levels, improve insulin sensitivity, and protect pancreatic β-cells from oxidative damage, making it a promising candidate for antidiabetic therapy [ 6 ]. Along with this, the ethnopharmacological relevance of C. myxa , the scientific validation of its antidiabetic activity, and the elucidation of underlying mechanisms remain limited. Some studies suggested that phytocompounds of C. myxa L. have the potential to inhibit key carbohydrate-metabolizing enzymes, including α-amylase, α-glycosidase, and DPP-4, or to mitigate oxidative stress and improve pancreatic tissue integrity [ 7 – 9 ]. Understanding these mechanisms is crucial for translating traditional knowledge into evidence-based therapies. The present study aims to address these gaps by investigating the antidiabetic potential of the methanolic extract of C. myxa fruits (MECMF). The comprehensive investigation not only provides scientific validation for the traditional use of C. myxa but also identifies active compounds, elucidates their potential mechanisms, and highlights the plant as a promising natural therapeutic agent for managing type 2 diabetes mellitus. Materials and methods The methodology was systemically categorized into three major steps, i.e., phytochemical profiling, in-silico evaluations, and in-vivo assessments. Phytochemical profiling Chemical profiling was following the collection of plant material, authentication, extraction, and LC–MS/MS analysis. Plant collection and extract preparation The unripe fruit of Cordia myxa (L.) was collected from Chouthpura, Khariberi, Balesar village of Jodhpur. The plant Cordia myxa was identified and authenticated by the Botanical Survey of India (BSI), Jodhpur, Rajasthan, with authentication number BSI/AZRC/I.12012/Tech./2021-22 (PI.Id.)/ 146 . Fruits were shade-dried, coarsely powdered, and extracted with methanol using Soxhlet apparatus for 48 hours [ 10 ]. The extract was concentrated under reduced pressure, yielding the methanolic extract of C. myxa fruits (MECMF), which was stored at 4°C until use [ 11 ]. Phytochemical analysis LC–MS/MS data were processed using UNIFI scientific library database. Peaks detected in both positive and negative ionization modes with intensities ≥ 3500 counts were extracted using a peak spacing tolerance of 0.0090 m/z to avoid noise and maintain adequate chromatographic resolution. Molecular masses were assigned based on MS/MS fragmentation patterns characteristic of the identified phytocompounds [ 12 ]. In-silico assessments The identified phytocompounds were docked against α-amylase, α-glycosidase, and DPP-4 to predict their binding affinities and interaction patterns. Pharmacokinetic and toxicity profiles were evaluated using SwissADME and ProTox-III web servers. Retrieval and preparation of targets and phytocompounds The X-crystal structure of Acarbose-bound human pancreatic alpha-amylase (2QV4), alpha glycosidase (2QMJ), and sitagliptin-bound DPP-4 (1X70) were retrieved from the Protein Data Bank ( https://www.rcsb.org/ ), and phytocompounds structures are retrieved from the PubChem database ( https://pubchem.ncbi.nlm.nih.gov/ ) [ 13 – 15 ]. Targeted proteins preparation was done by removing extra chains, water molecules, and bound heteroatoms. After that, polar hydrogen, Kollman charges were added, and assigned charges [ 16 ]. Ligand preparation entailed adding polar hydrogen assigned Gasteiger charges, and energy is minimized using the Avogadro tool[ 17 ]. Molecular docking analysis Docking simulations were performed using AutoDock 4.2 to assess the molecular interaction between targets and phytoconstituents [ 18 ]. The grid boxes were centered on the active site coordinates of the native co-crystallized ligands: X = 12.942, Y = 47.169, Z = 26.2 Å, X = -19.6, Y= -6.86, Z= -9.68 Å, and X = 41.18, Y = 51.04, Z = 35.62 Å for prepared α-amylase, α-glycosidase, and DPP-4, respectively, with a spacing of 0.375 Å. Docking accuracy was validated by redocking native ligands, achieving RMSD < 2 Å. Acarbose and sitagliptin served as standard inhibitors for α-amylase/α-glycosidaseand DPP-4, respectively [ 19 ]. Docked complexes were analyzed for binding affinity and interactions using Discovery Studio tools. ADME and toxicity prediction ADME analysis was carried out using SwissADME ( https://www.swissadme.ch/index.php ) to predict molecular weight, lipophilicity (iLogP, CLogP), hydrogen-bond donors/acceptors, topological polar surface area (TPSA), gastrointestinal absorption, and blood–brain barrier (BBB) permeability [ 20 – 22 ]. Toxicological profiles were assessed using the in silico Protox-III web server ( https://tox.charite.de/protox3/ ). The predictions included: Hepatotoxicity, nephrotoxicity, carcinogenicity, respiratory, mutagenicity, LD50 to evaluate the level of acute toxicity, and toxicity classes were assigned following Globally Harmonized System of Classification and Labelling of Chemicals (GHS) guidelines [ 23 ]. This predictive approach enhances the early-stage evaluation of chemical safety, aiding in the identification of promising drug candidates with minimal toxicity risks. Dynamics simulation MD simulations were performed using the SiBioLead web platform ( https://sibiolead.com/ ), which operates on a GROMACS-based backend. Each protein–ligand complex was parameterized with the OPLS/AA force field and solvated in an SPC water model within a dodecahedral box. The system was neutralized with Na⁺/Cl⁻ ions and adjusted to 0.15 mM ionic strength. Energy minimization was conducted using the steepest descent algorithm for 5000 steps, followed by NVT and NPT equilibration at 300 K and 1 bar for 100 ps. A 1 ns production run was performed using the MD integrator. The resulting XVG trajectories were used to extract RMSD and hydrogen-bond profiles, and mean ± SD values were calculated in Excel. In-vivo assessment Development of the type 2 diabetes mellitus animal model Animal model (weight 180–225 gm) was developed through the chemical induction method by following the use of nicotinamide and streptozotocin. Healthy adult male rats were treated with nicotinamide (200mg/kg) through intraperitoneal dispersal with 0.9% sodium chloride. Pretreated nicotinamide rats were used for the intraperitoneal administration of streptozotocin (60mg/kg) by dissolving it into sodium citrate buffer (4.5 PH), following the standard protocol through estimation of OGTT (Oral Glucose Tolerance Test). After 48 hours, by examining fasting glucose > 250 mg/dl confirmed diabetic induction [ 24 , 25 ]. Design of experimental protocol The experiment protocol was approved by the Institutional Ethical Committee (IAEC), Department of Zoology, Jai Narain Vyas University, Jodhpur (Rajasthan), India ( 1646/GO/Ere/S/12/CCSEA ). The animals were kept in spacious cages with a 12-hour light and 12-hour night cycle with 20–25°C temperature and 50–60% relative humidity. Standard rodent pellets and water were given in ad libitum[ 24 ]. The whole experiment was divided into four groups, consisting of six animals in each group, for the experimentation course of 28 days (four weeks) [ 26 ]. The extract was given orally (300 mg/kg Body Weight) with the help of an oral feeding cannula (18g ball tip curved), and doses were assessed by LD 50 values. Group I: Intact control or vehicle control (non-diabetic) Group II: Type 2 Diabetes mellitus control (diabetic). Group III: Diabetic + Sitagliptin (10 mg/kg Body Weight) Group IV: Diabetic + Methanol extract of C. myxa fruit (300 mg/kg Body Weight) Assessments of serum biochemical parameters After a 28-day experimental period, the rats, having undergone an overnight fast, were humanely euthanized using mild anesthesia. Blood samples were drawn from both the retro-orbital plexus and via cardiac puncture. The collected blood was centrifuged at 3000 rpm for 15 minutes to separate the serum, which was then stored at − 20°C for subsequent biochemical analysis [ 27 ]. Various serum-based assays were performed to evaluate glucose metabolism, including measurements of glucose and insulin levels, as well as lipid profile parameters. Additionally, oxidative stress markers—such as glutathione (GSH), superoxide dismutase (SOD), catalase, lipid peroxidation (LPO), and ferric reducing antioxidant power (FRAP)—were analyzed in relation to total protein content [ 28 ]. Quantitative estimations of glucose, total protein (TP), and lipid profile (total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL)) were carried out using commercial enzymatic kits provided by ERBA Diagnostic Pvt. Ltd. Estimation of HOMA IR, HOMA- \(\:\varvec{\beta\:}\) , and Quiki The quantification of insulin resistance and \(\:\beta\:\) -cell functioning was done by using the HOMA (Homeostatic Model Assessment) method. HOMA-IR (Insulin resistance), HOMA- \(\:\beta\:\) (beta cell-function, and QUICKI (quantitative insulin sensitivity check index) are valid estimations for insulin sensitivity in patients with type 2 diabetes [ 29 , 30 ]. $$\:\text{H}\text{O}\text{M}\text{A}-\beta\:\:\left(\text{%}\right)=\frac{20\times\:\text{F}\text{a}\text{s}\text{t}\text{i}\text{n}\text{g}\:\text{i}\text{n}\text{s}\text{u}\text{l}\text{i}\text{n}\:({\mu\:}\text{U}/\text{m}\text{L})}{\text{F}\text{a}\text{s}\text{t}\text{i}\text{n}\text{g}\:\text{g}\text{l}\text{u}\text{c}\text{o}\text{s}\text{e}\:\left(\frac{\text{m}\text{m}\text{o}\text{l}}{\text{L}}\right)-3.5}$$ $$\:\text{H}\text{O}\text{M}\text{A}-\text{I}\text{R}=\frac{\text{F}\text{a}\text{s}\text{t}\text{i}\text{n}\text{g}\:\text{i}\text{n}\text{s}\text{u}\text{l}\text{i}\text{n}\:\left(\frac{{\mu\:}\text{U}}{\text{m}\text{L}}\right)\times\:\text{F}\text{a}\text{s}\text{t}\text{i}\text{n}\text{g}\:\text{g}\text{l}\text{u}\text{c}\text{o}\text{s}\text{e}\:(\text{m}\text{m}\text{o}\text{l}/\text{L})}{22.5}$$ $$\:\text{H}\text{O}\text{M}\text{A}\:\text{S}\text{%}=\frac{1}{\text{H}\text{O}\text{M}\text{A}-\text{I}\text{R}}\times\:100$$ $$\:\text{Q}\text{U}\text{I}\text{C}\text{K}\text{I}=\frac{1}{{\text{L}\text{o}\text{g}}_{10}(\text{F}\text{a}\text{s}\text{t}\text{i}\text{n}\text{g}\:\text{i}\text{n}\text{s}\text{u}\text{l}\text{i}\text{n}\:\left({\mu\:}\text{U}/\text{m}\text{L})\right)+{\text{L}\text{o}\text{g}}_{10}(\text{F}\text{a}\text{s}\text{t}\text{i}\text{n}\text{g}\:\text{g}\text{l}\text{u}\text{c}\text{o}\text{s}\text{e}\:\left(\frac{\text{m}\text{g}}{\text{d}\text{L}}\right))}$$ Histology of pancreas Pancreatic tissues were collected from necropsied rats, washed with phosphate-buffered saline, and fixed in 10% neutral buffered formalin for 24 h. After washing, samples were dehydrated through graded ethanol (30–100%), cleared in xylene, and embedded in paraffin wax at 55–60°C. Sections of 5 µm thickness were prepared using a rotary microtome, stained with hematoxylin and eosin, following standard procedures [ 31 – 33 ], and mounted with DPX. The slides were examined under a phase-contrast microscope (Nikon Research Microscope System, Germany), and representative photomicrographs were captured at 200× magnification. Statistical analysis The biochemical and antioxidant parameters were expressed in terms of mean ±standard error mean[ 34 ]. Statistical analysis was performed using two-way and one-way analysis of variance (ANOVA), followed by Tukey’s test to evaluate the statistical differences between the means of the various groups. A p-value ≤ 0.05 was considered significant. Statistical analyses and graphical representations were conducted using GraphPad Prism-7 software, and Histological photographs were analyzed using ImageJ software. Results Identification of phytoconstituents through LC-MS/MS LC–MS profiling of the test extract revealed the occurrences of twelve leading phytoconstituents (Table 1 & Fig. 1 A-B). The identified compounds included polyphenols (ferulic acid, caffeic acid, and rosmarinic acid), flavonoids (catechin and rutin), triterpenoids (α-amyrin), sterols (β-sitosterol), and fatty alcohols/acids (octacosanol and oleic acid). Importantly, Cordia -specific metabolites Cordiaquinone C and Cordiaquinone G were identified at retention times of 1.77 min and 9.27 min. The detected compounds spanned retention times from 1.60 to 24.74 min with corresponding m/z values consistent with their molecular weights. Table 1 Identified masses from UPLC-QTOF mass spectroscopy constituents in the C. myxa methanolic extract in negative and positive electron ionization mode S.No. Identified compound Name Formula Monoisotopic mass (g/mol) Retention time (min) m-z/ m + z values 1. Ferulic acid C 10 H 10 O 4 194.2 1.93 min 217.3 2. Alpha-amyrin C 30 H 50 O 426.7 24.74 min 426.5 3. Octacosanol C 28 H 58 O 410.8 1.60 min 387.3 4. Caffeic acid C 9 H 8 O 4 180.16 1.77 min 157.2 5. β- sitosterol C 29 H 50 O 414.7 1.77 min 391.3 6. Cordiaquinone C C 26 H 30 O 4 406.5 1.77 min 383.4 7. Catechin C 15 H 14 O 6 290.27 1.98 min 289.3 8. Oleic acid C 18 H 34 O 2 282.5 1.98 min 259.3 9. Syringaldehyde C 9 H 10 O 4 182.2 5.10 min 181.2 10. Rosmarinic acid C 18 H 16 O 8 360.3 8.38 min 359.3 11. Cordiaquinone G C 21 H 26 O 4 342.4 9.27 min 343.4 12. Rutin C 27 H 30 O 16 610.5 24.35 min 587.7 In-silico analysis Molecular docking through Autodock4 The re-docking validation revealed that Alpha-amylase, Alpha glycosidase, and DPP4 re-docked native ligand exhibited an RSMD value of 1.2Å, 0.7 Å, 0.5 Å, and with a binding energy of -11.7, -8.61, -8 Kcal/mol, respectively (Supplementary file 1). Docking investigations identified three bioactive constituents from Cordia myxa exhibiting notable affinity toward carbohydrate-metabolizing enzymes. Cordiaquinone-C displayed a binding energy of -9.92 kcal mol⁻¹ with α-amylase, approaching the reference inhibitor Acarbose (-11.7 kcal mol⁻¹). Cordiaquinone-G bound effectively with α-glycosidase (-8.75 kcal mol⁻¹), slightly exceeding the affinity of Acarbose (-8.61 kcal mol⁻¹). Likewise, β-sitosterol showed a binding score of -9.32 kcal mol⁻¹ against DPP-IV, surpassing the standard compound (-8.0 kcal mol⁻¹). These findings indicate a strong potential of the identified compounds to interact with their respective enzymatic targets. The interaction profiles, including hydrogen bonds and hydrophobic contacts, were visualized using Discovery Studio Visualizer, confirming stable and well-oriented binding within the catalytic pockets of the enzymes (Table 2 – 4 ; Fig. 2 A-F). Consequently, the α-amylase–Cordiaquinone-C, α-glycosidase–Cordiaquinone-G, and DPP-IV–β-sitosterol complexes were selected for molecular dynamics simulations to further assess their structural stability, binding persistence, and conformational dynamics under standard parameters. Table 2 The binding energies obtained with identified phytocompounds along with interacting residues and bond length of molecular interaction of methanolic extract with α-amylase (2QV4) Phytoconstituents α-amylase (binding energy) Interacting Residues Bond types Distance Alpha-amyrin -9.83 Tyr62, Trp59 Pi-Sigma 3.93, 4.00 Ferulic acid -4.55 Tyr151, Asp197, Lys200, His101, Leu162, Ala198, Glu233 H-bond, Alkyl, Pi-Anion, Pi-Alkyl 2.02, 1.93, 1.86, 4.54, 4.87, 5.10, 3.16 Octacosanol -3.57 Tyr62, Trp58, Trp59, Leu165, Lys200, His201, Ile235, His305 Pi-Sigma, Pi-Alkyl, Alkyl 3.43, 5.32, 5.26, 5.41, 4.74, 4.92, 5.36, 5.22, 4.12, 4.42, 3.98, 5.19, 4.34 Caffeic acid -4.97 Tyr151, Asp197, Lys200, Ala198, Glu233 H-bond, Pi-Alkyl, Pi-Anion 2.06, 1.90, 1.90, 1.84, 5.01, 3.18 Cordiaquinone C -9.92 Gln63, His201, Leu165, Lys200, Ile235, Glu233 H-bond, Alkyl, CH-bond, Pi-Alkyl, Pi-Sigma 1.84, 2.23, 5.02, 3.58, 5.16, 4.12, 4.87, 3.54 Syringaldehyde -4.62 Tyr151, Ile235, Lys200, Leu162, His201 H-bond, Pi-Pi T-shaped, Pi-Cation, Alkyl, Pi-Sigma, Pi-Alkyl 2.13, 3.89, 1.74, 3.75, 2.40, 5.16, 5.39, 4.64, 2.27 Rosmarinic acid -6.25 His15, Val42, Arg337, Ser43, Arg195, Gln41, Tyr62, Asp96, Asn298, His299 H-bond, Van der Waals, Pi-Sulfur, Unfavourable Bump, Pi-Lone Pair, Amide-Pi Stacked, CH-bond, Pi-Alkyl, Pi-Cation 2.78, 2.59, 2.83, 2.00, 3.04, 2.47, 5.21, 2.29, 1.42, 6.30, 2.02, 2.47, 2.18, 2.56 Beta-sitosterol -9.63 Asp300, Trp58, Trp59, Tyr62 H-bond, Pi-Alkyl 2.06, 5.38, 4.10, 4.57 Catechin -6.79 Gln63, Tyr62, Asp197, Glu233, Trp59, Ala198 H-bond, Pi-Anion, Unfavourable Doner-Doner, Pi-Pi Stacked 1.98, 1.82, 4.43, 2.00, 2.47, 4.50, 2.13, 2.50, 4.82, 2.52 Cordiaquinone G -8.36 Lys200, Asp300, Ile235, Leu162, Ala198, His201, Glu233 H-bond, Pi-Sigma, Unfavourable Acceptor-Acceptor, Pi-Pi T-shaped, Pi-Cation, Pi-Alkyl, Pi-Anion 2.50, 4.50, 1.94, 2.05, 3.61, 5.40, 4.99, 4.83, 3.34, 4.07, 2.97, 4.05 Oleic acid -4.07 Lys200, Trp59, Tyr62, Leu162, Leu165, Ala198, His201, Ile235 H-bond, Pi-Alkyl, Alkyl 2.20, 4.93, 3.90, 5.46, 4.88, 5.35, 4.36, 5.28, 5.37 Rutin -7.45 Ty62, Gln63, Arg195, Asp197, Glu233, Asp300, His305, Gly306, Leu165 H-bond, Pi-Alkyl, CH-bond 1.83, 2.01, 1.85, 2.18, 1.66, 2.03, 2.46, 2.12, 2.56,1.80, 1.89, 2.00, 3.45, 5.16 Table 3 The binding energies obtained with identified phytocompounds along with interacting residues and bond length of molecular interaction of methanolic extract with α-glycosidase (2QMJ) Phytoconstituents α-glycosidase (binding energy) Interacting Residues Bond types Distance Alpha-amyrin -6.84 Tyr605, Phe450 H-bond, Pi-Sigma 1.93, 3.43, 3.98 Ferulic acid -3.25 Gln603, Tyr605 H-bond, Pi-Alkyl 1.93, 2.09, 4.53 Octacosanol -2.12 Trp539, Asp542, Phe575, Tyr299, Trp406, Phe450, Lys480, His600 H-bond, Pi-Sigma, Alkyl, Pi-Alkyl 1.81, 1.83, 3.95, 4.99, 5.10, 4.04, 5.09, 4.98, 5.50, 4.35, 4.19, 4.04, 4.77, 5.28 Caffeic acid -3.42 Asp203, Asp327, Arg526, His600, Tyr299, Asp443, Met444 H-bond, Pi-Anion, Sulfur-X, Pi-Pi T-shaped 1.74, 1.72, 1.61, 2.18, 1.85, 5.73, 3.47, 3.03 Cordiaquinone C -7.49 Arg202, Asp203, Ile328, Ile364, Trp406, Lys480 H-bond, Alkyl, Pi-Anion, Pi-Alkyl 4.89, 3.17, 3.59, 4.20, 5.06, 5.15, 4.52 Syringaldehyde -5.39 Arg526, Asp542, Asp327, Asp443, Met444, Trp539, Phe575, His600, Asp571 H-bond, Alkyl, CH-bond, Pi-Alkyl, Pi-Anion 2.10, 2.10, 2.10, 3.16, 3.10, 2.99, 3.23, 5.21, 5.69, 4.07, 3.97, 3.68 Rosmarinic acid -7.18 Asp203, Asp327, Arg334, Trp406, Asp443, Arg526, Tyr605, Phe450 H-bond, Pi-Pi T-shaped, Pi-Pi Stacked 1.84, 2.01, 1.87, 1.83, 2.19, 4.50, 1.61, 1.72, 2.85, 2.10, 2.26, 5.97 Beta-sitosterol -7.82 Tyr299, Trp406, Trp441, Met444, Trp539, Phe575, His600 Pi-Sigma, Pi-Alkyl, Alkyl 3.64, 5.07, 5.18, 4.96, 5.67, 4.88, 4.75 Catechin -6.78 Asp443, Arg526, Asp542, Gln603, Tyr299, Trp406 H-bond, Pi-Doner H-bond, Pi-Anion, Pi-Pi T-shaped 1.85, 1.77, 1.85, 4.49, 1.70, 1.83, 3.03, 5.50, 4.98 Cordiaquinone G -8.75 Asp327, Asp542, His600, Tyr299, Gly602 H-bond, Pi-PI T-shaped, CH-bond 1.72, 2.23, 1.78, 4.69, 5.21, 3.05 Oleic acid -3.5 Arg334, Gln603, Tyr605, Phe575 H-bond, Pi-Alkyl 2.01, 1.90, 2.18, 1.99, 4.57, 4.01 Rutin -8.15 Asp203, Asp327, Arg334, Trp406, Asp443, Asp542, His600, Tyr605, Phe450 H-bond, Pi-Pi T-shaped, Pi-Pi Stacked 2.16, 1.74, 1.92, 1.86, 2.53, 2.26, 2.36, 2.06, 2.10, 2.28, 5.93 Table 4 The binding energies obtained with identified phytocompounds along with interacting residues and bond length of molecular interaction of methanolic extract with DPP-4 (1X70) Phytoconstituents DPP-4 (binding Energy) Interacting Residues with DPP-4 Bond types Distance Alpha-amyrin -7.41 Tyr547, Arg358 H-bond, Alkyl 1.90, 5.47 Ferulic acid -4.71 Glu206, Val207, Arg358, Arg669, Ser209 H-bond, Pi-Lone Pair, CH-bond 1.90, 2.75, 2.11, 1.94, 1.89, 3.29 Octacosanol -2.34 Val207, Phe357, Tyr547, Tyr662, Tyr666, Val711, His740 H-bond, Alkyl, Pi-Sigma, Pi-Alkyl 2.03, 5.01, 5.20, 4.82, 5.43, 3.50, 4.35, 5.37, 4.16 Caffeic acid -5.14 Val207, Glu206, Arg358, Arg669, Phe357 H-bond, Pi-Pi Stacked, Unfavourable Acceptor-Acceptor 1.96, 1.86, 1.98, 2.83, 3.69, 2.40, 4.16 Cordiaquinone C -8.57 Tyr547, Arg358, Tyr631, Val656, Trp659, Tyr662, Tyr666, Ser630 H-bond, Alkyl, CH-bond, Pi-Alkyl, Pi-Sigma 1.87, 4.97, 5.29, 4.68, 4.49, 3.77, 3.94, 3.13 Syringaldehyde -4.55 Arg125, Glu205, Ser630, Tyr547, Tyr666, Glu206 H-bond, Pi-Alkyl, CH-bond 2.33, 2.25, 2.43, 5.08, 4.60, 2.92 Rosmarinic acid -7.15 Arg125, Glu206, Ser630, Arg669 Tyr666, Phe357, Tyr662, His740 H-bond, Pi-Pi Stacked, CH-bond, Pi-Pi T-shaped, Unfavourable Doner-Doner 1.99, 2.87, 1.67, 2.20, 2.09, 2.00, 6.14, 2.15, 5.22, 5.04, 4.54, 3.77 Beta-sitosterol -9.32 Phe357, Tyr662, Tyr666, Arg358 Unfavourable Doner-Doner, Pi-Alkyl 4.99, 5.15, 5.10, 4.74, 5.47, 1.72 Catechin -7.51 Glu205, Phe357, Ser630, Tyr662, Tyr666, Tyr631 H-bond, Pi-Alkyl, Pi-Pi T-shaped, Amide-Pi Stacked, Pi-Pi Stacked, van der Waals 2.05, 2.12, 4.99, 4.51, 4.48, 5.63, 4.78, 5.37 Cordiaquinone G -6.96 Glu205, Asn710, Arg358, Tyr666 H-bond, Pi-Sigma, CH-bond, Pi-Alkyl 2.14, 3.05, 3.07, 5.38, 3.68 Oleic acid -3.97 Arg358, Phe357, Tyr631, Val656, Trp659, Tyr662, Tyr666, His740 H-bond, Pi-Alkyl, Alkyl 2.65, 2.73, 4.71, 5.14, 5.35, 5.23, 5.38, 4.11, 4.31, 5.31 Rutin -6.33 Glu206, Phe357, Arg358, Tyr547, Cys551, Tyr585, Tyr666, Arg669, Glu205 H-bond, Pi-Alkyl, CH-bond 1.75, 2.34, 2.08, 2.63, 5.00, 2.18, 2.84, 2.03, 2.47, 2.42, 6.14, 3.60 ADME and toxicity prediction According to the ADME study, the derivatives Alpha-amyrin, Cordiaquinone C, and Cordiaquinone G, which exhibited favorable binding affinities with the target proteins, adhered to the Lipinski Rule of Five with no violations. Beta-sitosterol exhibited favorable binding affinities with the target proteins, adhered to the Lipinski Rule of Five with 1 violation. These Cordia-specific quinones show high intestinal absorption and cross the BBB as per BOILED-Egg prediction (Fig. 3 ). Results of ADME analysis are tabulated in Table 5 . The toxicity prediction of the alpha amyrin exhibited nephron toxicity and respiratory toxicity. Cordiaquinone C and Cordiaquinone G show respiratory toxicity. Beta-sitosterol shows neurotoxicity alerts (Table 6 ). Table 5 Molecular Weight, Lipophilicity, Hydrogen Bonding Features, TPSA, GI/BBB Predictions, and Lipinski Compliance of the Selected Compounds using SwissADME web server Compound MW iLogP CLogP HBA HBD TPSA GI/BBB Lipinski rule Alpha-amyrin 426.72 4.8 7.06 1 1 20.23 Å Low & No Yes, 0 violation Ferulic acid 194.18 1.62 1.36 4 2 66.76 Å High & Yes Yes, 0 violation Octacosanol 410.76 7.2 9.8 1 1 20.23 Å Low & No Yes, 1 violation Caffeic acid 180.16 0.97 0.93 4 3 77.76 Å High & No Yes, 0 violation Cordiaquinone C 406.51 3.76 4.93 4 0 60.44 Å High & Yes Yes, 0 violation Syringaldehyde 182.17 1.66 0.93 4 1 55.76 Å High & Yes Yes, 0 violation Rosmarinic acid 360.31 1.48 1.58 8 5 144.52 Å Low & No Yes, 0 violation Beta-sitosterol 414.71 5.05 7.24 1 1 20.23 Å Low & No Yes, 1 violation Catechin 290.27 1.33 0.83 6 5 110.38 Å High & No Yes, 0 violation Cordiaquinone G 342.43 2.73 2.94 4 2 74.6 Å High & Yes Yes, 0 violation Oleic acid 282.46 4.01 5.65 2 1 37.3 Å High &No Yes, 1 violation Rutin 610.52 0.46 -1.51 16 10 269.43 Å Low & No No, 3 violations Acarbose 807.75 -0.11 -0.11 24 17 400.32 Å Low & No No, 3 violations Sitagliptin 407.31 2.35 2.51 10 1 77.04 Å High & Yes Yes, 0 violation Table 6 Predicted Toxicological Profiles of the Selected Compounds by Protox 3.0 web tool. Phytoconstituents Hepato- Toxicity Neuro- Toxicity Nephro- Toxicity Carcino- Toxicity Resp- Toxicity Muta- Toxicity LD50 (mg/kg) Toxicity class Alpha-amyrin Inactive Inactive Active Inactive Active Inactive 5000 5 Ferulic acid Inactive Inactive Active Inactive Inactive Inactive 1772 4 Octacosanol Inactive Inactive Inactive Inactive Inactive Inactive 1000 4 Caffeic acid Inactive Inactive Active Active Inactive Inactive 2980 5 Cordiaquinone C Inactive Inactive Inactive Inactive Active Inactive 2000 4 Syringaldehyde Inactive Inactive Active Inactive Inactive Inactive 2000 4 Rosmarinic acid Inactive Inactive Active Inactive Inactive Inactive 5000 5 Beta-sitosterol Inactive Active Inactive Inactive Active Inactive 890 4 Catechin Inactive Inactive Active Inactive Active Inactive 10000 6 Cordiaquinone G Inactive Inactive Inactive Inactive Active Inactive 260 3 Oleic acid Inactive Inactive Inactive Inactive Inactive Inactive 48 2 Rutin Inactive Inactive Active Inactive Active Inactive 5000 5 Sitagliptin Inactive Active Inactive Inactive Active Inactive 2500 5 Acarbose Active Inactive Active Inactive Active Inactive 2000 4 Dynamics simulation The backbone RMSD plots (Figs. 4 A–C) indicate that all protein–ligand complexes rapidly achieved structural equilibrium and remained stable throughout the 1-ns simulation. Likewise, the hydrogen-bond profiles (Figs. 4 D–F) reveal persistent and well-defined polar interactions across the trajectory. The combination of early RMSD convergence and consistent hydrogen-bonding patterns confirms that the complexes attained a stable binding state, thereby supporting the reliability of the 1-ns MD results and validating the structural interpretations drawn from this timeframe. Structural stability assessed by RMSD α-Amylase complexes As shown in Fig. 4 A, Acarbose displayed a smooth and tightly clustered RMSD trajectory (µ = 0.1128 ± 0.0077 nm), reflecting a stable binding mode with minimal structural perturbation. Cordiaquinone C showed slightly higher fluctuations (µ = 0.1244 ± 0.0118 nm) yet remained within the acceptable range for stable complexes (< 0.20 nm). The marginally elevated RMSD variance of cordiaquinone C suggests increased local flexibility but not destabilization of the protein fold. α-glycosidase complexes In Fig. 4 B, Acarbose again exhibited consistent stability (µ = 0.1266 ± 0.0074 nm). Cordiaquinone G demonstrated comparable stability with an RMSD mean of 0.1244 ± 0.0118 nm, indicating that the ligand adopted a stable conformation without inducing backbone deviation. The close similarity between the two ligands reflects robust accommodation within the α-glycosidase catalytic cleft. DPP-4 complexes As shown in Fig. 4 C, sitagliptin exhibited moderate fluctuations (µ = 0.1372 ± 0.0165 nm) but stabilized early and remained steady thereafter. β-Sitosterol showed a slightly higher RMSD (µ = 0.1420 ± 0.0204 nm), which is expected given its bulky hydrophobic structure. Nevertheless, its RMSD stability indicates effective retention within the DPP-4 binding pocket. Hydrogen bond analysis α-Amylase complexes As shown in Fig. 4 D, Acarbose formed recurrent hydrogen bonds, frequently maintaining 1–4 simultaneous interactions with an average of 1.16 ± 0.94. Cordiaquinone C, however, showed sparse and short-lived hydrogen bonding (0.21 ± 0.46), indicating that its stabilization relies more on hydrophobic or aromatic interactions rather than persistent polar contacts. Despite lower H-bond occupancy, the RMSD stability suggests that cordiaquinone C remains well anchored within the active site. α-glycosidase complexes In Fig. 4 E, Acarbose again displayed strong hydrogen bonding (µ = 1.31 ± 0.76), consistent with its polar nature. Cordiaquinone G exhibited moderate hydrogen bonding (µ = 0.99 ± 0.70) that occurred intermittently but remained dynamically relevant. The stable RMSD and moderate H-bonding indicate a balance of hydrophobic and polar contacts in Cordiaquinone G enzyme interactions. DPP-4 complexes Hydrogen bonding in DPP-4 was minimal for both ligands (β-Sitosterol and sitagliptin) (Fig. 4 F). Sitagliptin exhibited very low mean H-bond occupancy (0.028 ± 0.164), consistent with its pharmacophore design, where hydrophobic and π-stacking interactions dominate protein engagement. β-Sitosterol, being structurally hydrophobic, showed slightly higher but still low H-bonding (0.086 ± 0.280). Despite minimal polar interactions, both complexes remained structurally stable, reflecting the hydrophobic nature of the DPP-4 binding cleft. In-vivo assessments Biochemical parameters assessments Lipid profiling and dyslipidemia indices The treatment produced a marked improvement in the lipid profile of diabetic rats (Fig. 5 ). Triglyceride (TG) and total cholesterol (TC) concentrations were significantly reduced in the treated group compared with the diabetic control, accompanied by a clear decline in LDL and VLDL levels. Although HDL levels showed only marginal and statistically non-significant changes, the overall lipid-modulating effect was evident, reflecting the treatment’s potential to counteract diabetes-induced dyslipidemia. Consistently, the atherogenic indices AIP (Atherogenic Index of Plasma), CRI-I, CRI-II (Castelli Risk Index I & II), and AC (Atherogenic Coefficient) were significantly lowered following treatment, indicating enhanced lipid homeostasis and a diminished risk of diabetes-related cardiovascular complications (Fig. 6 ). Antioxidants The treated group exhibited a significant elevation in GSH and FRAP levels compared to the diabetic control, indicating improved antioxidant status. Total protein (TP) levels showed non-significant variation among the groups, while LPO levels were markedly reduced in the treated group, suggesting attenuation of lipid peroxidation. The results of the treated group reflect enhanced oxidative defense and renal protection relative to the diabetic group (Figs. 7 – 8 ). HOMA indices HOMA indices evaluation shows that insulin levels, β-cell function (HOMA-β), and insulin sensitivity (QUICKI) declined in the diabetic group compared to the control group, whereas the treatment group and sitagliptin reduced insulin resistance significantly. Additionally, the treated and standard group showed notable improvement in blood glucose regulation and insulin resistance (HOMA-IR), demonstrating better glycemic control (Fig. 9 – 10 ). 3.3.2 Histology Compact and organized histoarchitecture of the pancreases were composed of islets of the Langerhans, exocrine cells, blood vessels, and connective tissues in the vehicle control group. Each islet is situated in a cellular plate with anastomosing connections. In the diabetic group, the pancreas showed vacuolations with different degrees of degeneration in the cellular content of the islet. Whereas, the treatments of the test extract and sitagliptin caused significant ameliorations in cellular mass by subsiding the vacuolations and diminishing the degenerative changes (Fig. 11 ). Discussion Herbal extracts are assemblages of the potent phytocompounds that work synchronically or independently with specific targets or concerned combined characteristics to support the therapeutics[ 35 ]. Subsequently, the phytochemical profiling of the test extract shown existence of potent phytocompounds with different patterns and features, including phenolic acids, flavonoids, sterols, terpenoids, and the characteristic quinones Cordiaquinone C and Cordiaquinone G, each of which is known for its biological relevance in oxidative balance and metabolic regulation, as depicted by the previous studies [ 4 , 5 , 36 ]. This broad chemical profile points toward a multifaceted mode of action rather than reliance on a single dominant compound. Accordingly, the mode of action of small-molecule phytocompounds depends on the interaction capabilities with active sites and the stabilities of the complexes, which resulted in the biological activities[ 37 ]. The molecular docking showed that the key constituents of the extract interact compatibly with α-amylase, α-glycosidase, and DPP-4, displaying through binding energies, numbers of hydrogen bonds, and bond lengths. These interactions were executed by hydrophobic interactions, aromatic stacking, and selective hydrogen bonding within the catalytic regions of the enzymes[ 38 ]. The interactions were further validated through key molecular dynamic simulation parameters such as RSMD and consistency of hydrogen bonding status. RMSD (Root-Mean-Square Deviation) is a basic calculation that calculates the average distance between the atoms of a superimposed protein or molecule in different conformations [ 39 , 40 ]. Accordingly, the interpretations of the RSMD of three complexes validate the interaction capabilities. The values of RSMD of complexes were confirmed by the status of hydrogen bonding profiles. The hydrogen bond (H-bond) stability is explained by tracking donor-acceptor distances and angles over time, using calculations such as possession and firmness represented through their persistence against thermal instabilities, expressing their role in structure and function, frequently heightened for prediction beyond simple energy [ 41 ]. Consequently, the screened potent small phytocompounds followed the five rules of Lipinski as represented by the drug likeness characteristics through filter competency [ 42 ]. Subsequently, the β-sitosterol was performed considerable interactions with three selected targets whereas the significant interaction was made with DPP-4. Therefore, further experimentations were performed for the in-vivo assessments. The in-vivo studies revealed that the cytotoxic mode of action of streptozotocin in nicotinamide treated animal resulted in hyperglycemia through dysfunctions of β-cells, reduced sensitivity, and insulin resistance[ 43 ]. The treatment of test extract caused significant improvements in HOMA indices (insulin resistance, β-cell sensitivity, and function) as revealed through pancreatic histology. Supportively, the oxidative stress was reduced through the treatments of test extract and sitagliptin, which indicates the synchronizing mode of action of the potent phytocompounds. It is depicted through numerous studies that reduced oxidative stress promotes restorations by subsiding the degenerative changes through scavenging the free radicals and support to regularizing of the key metabolic pathways[ 44 ]. The glucose and lipid metabolisms are linked with each other’s which are altered significantly through the treatments of the test extract. It can be represented through interactions of small molecules phytocompound with key metabolic enzymes (α-amylase, α-glycosidase, and DPP-4), and their inhibition resulted in reduced glucose levels as well as improved lipid profile, as reported by earlier studies [ 45 – 47 ]. The collective interpretations of the improved histoarchitectures of the pancreases, reduced glucose levels, ameliorated lipid profile, and improved oxidative stress can be expressed through interactions of selected phytocompounds, which have significant capabilities to ameliorate the hyperglycemia by following the synchronized action through multitargeted pathways. Conclusion The study represents the existence of the twelve potent phytocompounds of the methanolic fruit extract of Cordia myxa L. (MECMF), which have the capabilities to interact with selected targets particularly β-sitosterol, Cordiaquinone C, and Cordiaquinone G that displayed strong inhibitory potential against DPP-4, α-amylase, and α-glycosidase, respectively. Subsequently, in-vivo evaluations validate the multitargeted interactions of the selected coonhounds through biochemical as well as histological assessments. These integrated findings substantiate the traditional use of C. myxa and establish MECMF as a promising multitarget natural therapeutic candidate for managing type 2 diabetes mellitus. Further isolation and characterization of its active compounds may accelerate the development of safe, plant-derived antidiabetic agents. Declarations Acknowledgement Authors sincerely acknowledged the kind cooperation of the department of Zoology, Jai Narain Vyas University, Jodhpur (Rajasthan) for the providing required facilities and ethical approval. Author’s contribution Chandra Kala & Kavita Kumari Gaur – Investigation and experimentations; Kamlesh Kumar, Rajat Raja and Kirti Rathore – Data compilation and original drafting; Surbhi Ranga & Mukesh Kumar – Review & Editing and Heera Ram – Conceptualization & Supervision. Data availability statement Data can be provided on the request with permission of the research team for positive rational. 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Advanced drug delivery reviews , 46 (1–3), 3–26. https://doi.org/10.1016/S0169-409X(00)00129-0 Rais, N., Ved, A., Ahmad, R., Parveen, K., Gautam, G. K., Bari, D. G., … Singh, A.P. (2022). Model of Streptozotocin-nicotinamide Induced Type 2 Diabetes: A Comparative Review. Current diabetes reviews , 18 (8). https://doi.org/10.2174/1573399818666211117123358. Chaudhary, P., Janmeda, P., Docea, A. O., Yeskaliyeva, B., Abdull Razis, A. F., Modu,B., … Sharifi-Rad, J. (2023). Oxidative stress, free radicals and antioxidants: potential crosstalk in the pathophysiology of human diseases. Frontiers in Chemistry , 11 , 1158198. https://doi.org/10.3389/FCHEM.2023.1158198/FULL. Riyaphan, J., Pham, D. C., Leong, M. K., & Weng, C. F. (2021). In Silico Approaches to Identify Polyphenol Compounds as α-Glucosidase and α-Amylase Inhibitors against Type-II Diabetes. Biomolecules , 11 (12), 1877. https://doi.org/10.3390/BIOM11121877 Chhabria, S., Mathur, S., Vadakan, S., Sahoo, D. K., Mishra, P., & Paital, B. (2022). A review on phytochemical and pharmacological facets of tropical ethnomedicinal plants as reformed DPP-IV inhibitors to regulate incretin activity. Frontiers in Endocrinology , 13 , 1027237. https://doi.org/10.3389/FENDO.2022.1027237/FULL Ansari, P., Hannon-Fletcher, M. P., Flatt, P. R., & Abdel-Wahab, Y. H. A. (2021). Effects of 22 traditional anti-diabetic medicinal plants on DPP-IV enzyme activity and glucose homeostasis in high-fat fed obese diabetic rats. Bioscience Reports , 41 (1), BSR20203824. https://doi.org/10.1042/BSR20203824 Supplementary Files Supplementaryfile118.01.2026.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Resubmit revised form; Major revisions required 21 Mar, 2026 Reviewers agreed at journal 25 Feb, 2026 Reviewers invited by journal 25 Feb, 2026 Editor invited by journal 24 Feb, 2026 Editor assigned by journal 19 Feb, 2026 First submitted to journal 17 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8824801","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":597227002,"identity":"4ceabedd-74fa-4ccc-99b1-4c07f308c4af","order_by":0,"name":"Chandra Kala","email":"","orcid":"","institution":"Jai Narain Vyas University Faculty of Science","correspondingAuthor":false,"prefix":"","firstName":"Chandra","middleName":"","lastName":"Kala","suffix":""},{"id":597227003,"identity":"6d13a50d-ac42-475d-984a-220568dac5ca","order_by":1,"name":"Kamlesh Kumar","email":"","orcid":"","institution":"Jai Narain Vyas University Faculty of Science","correspondingAuthor":false,"prefix":"","firstName":"Kamlesh","middleName":"","lastName":"Kumar","suffix":""},{"id":597227004,"identity":"9976bef8-b1f0-43ae-b828-fda7320c739c","order_by":2,"name":"Kirti Rathore","email":"","orcid":"","institution":"Jai Narain Vyas University Faculty of Science","correspondingAuthor":false,"prefix":"","firstName":"Kirti","middleName":"","lastName":"Rathore","suffix":""},{"id":597227005,"identity":"4fc430fe-7ef0-42f0-a3c0-37dfd8642c95","order_by":3,"name":"Kavita Kumari Gaur","email":"","orcid":"","institution":"Jai Narain Vyas University Faculty of Science","correspondingAuthor":false,"prefix":"","firstName":"Kavita","middleName":"Kumari","lastName":"Gaur","suffix":""},{"id":597227006,"identity":"662e2786-d0bc-42f5-b2ca-027e06a61d7c","order_by":4,"name":"Surbhi Ranga","email":"","orcid":"","institution":"Ananya Medical College","correspondingAuthor":false,"prefix":"","firstName":"Surbhi","middleName":"","lastName":"Ranga","suffix":""},{"id":597227007,"identity":"d61626ef-e5c7-4e6a-9720-439883c616c3","order_by":5,"name":"Mukesh Kumar","email":"","orcid":"","institution":"Central University of Punjab","correspondingAuthor":false,"prefix":"","firstName":"Mukesh","middleName":"","lastName":"Kumar","suffix":""},{"id":597227008,"identity":"dcb14e7d-250c-4870-aa47-0c15cef5c810","order_by":6,"name":"Rajat Raja","email":"","orcid":"","institution":"Mizoram University","correspondingAuthor":false,"prefix":"","firstName":"Rajat","middleName":"","lastName":"Raja","suffix":""},{"id":597227009,"identity":"a5482a84-4577-46ab-8e05-28a3d068c0b3","order_by":7,"name":"Heera Ram","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuklEQVRIiWNgGAWjYBACAzBZwQbh8YARUVrOkKyFsY0BroUwMJc+wPzh4zy+PIMbCYwP3rYxyJgT0mLZl8BgOHMbWzFQC7Ph3DYGHssGQg47w8CQzLuNLXHmjAQ2aV6gFoMDRGg5zDsHrIX9N7FaGJt5G9gS+yUS2JiJ1MLYzDjjGFALz8NmyTnnJIjRwnz4w4eaY4lt7MkHP7wps7EnqAUYKQ1A4hiMIUFQPQzUEK1yFIyCUTAKRiAAABB3OCAsGr/wAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-6743-1321","institution":"Jai Narain Vyas University Faculty of Science","correspondingAuthor":true,"prefix":"","firstName":"Heera","middleName":"","lastName":"Ram","suffix":""}],"badges":[],"createdAt":"2026-02-09 01:44:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8824801/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8824801/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104401035,"identity":"6b1f136a-bf6a-4d8d-adb0-9c5070a59f4f","added_by":"auto","created_at":"2026-03-11 12:11:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82163,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA: \u003c/strong\u003eFigure 1. UPLC–QTOF (LC–MS/MS) chromatograms of \u003cem\u003eCordia myxa\u003c/em\u003e methanolic extract in positive (+) ionization modes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB: \u003c/strong\u003eFigure 1. UPLC–QTOF (LC–MS/MS) chromatograms of \u003cem\u003eCordia myxa\u003c/em\u003e methanolic extract in negative (-) ionization modes.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/b8dacf776d426faf961f58c1.png"},{"id":103881110,"identity":"76fcaac0-3c12-4577-aebd-cd3ea00e10a1","added_by":"auto","created_at":"2026-03-04 05:25:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":323189,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA-F: \u003c/strong\u003eMolecular interaction visualization of α-amylase-cordiaquinone-C (A-B), α-glycosidase-cordiaquinone-G (C-D), and DPP4-beta-sitosterol (E-F) complexes displaying different bond types and their interaction distances within the active site pocket.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/07f981b550445c33ddce26e1.png"},{"id":103881111,"identity":"2a1f5a67-5dcb-4775-a569-6cc234a227ff","added_by":"auto","created_at":"2026-03-04 05:25:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":69796,"visible":true,"origin":"","legend":"\u003cp\u003eBOILED-Egg model depicting Blood–Brain Barrier permeability and gastrointestinal absorption of \u003cem\u003eCordia\u003c/em\u003e-\u003cem\u003especific compounds\u003c/em\u003e and beta-sitosterol predicted by the SwissADME web server.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/30b19c75f79e7520a386fb40.png"},{"id":103881095,"identity":"a2a9b734-fcc7-41fb-8805-c5b8451c3674","added_by":"auto","created_at":"2026-03-04 05:25:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":272660,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA-F.\u003c/strong\u003e Molecular dynamics analysis of protein–ligand complexes showing backbone RMSD and hydrogen bond stability over a 1 ns simulation for standard drugs and test compounds.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/1443128033a1662634f7170b.png"},{"id":103881109,"identity":"6324056b-6836-46c7-b9f1-d8349db844cd","added_by":"auto","created_at":"2026-03-04 05:25:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":85023,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of methanolic extract on lipid profile parameters (TG, TC, HDL, LDL, and VLDL). Data are presented as mean ± SEM (n = 6). Statistical analysis was performed using two-way ANOVA. (d, p ≤ 0.0001 compared with the control group; c, p ≤ 0.001 compared with the control group; s, p ≤ 0.0001 compared with the diabetic control group; t indicates a non-significant difference compared with the diabetic control group).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/bf4fa0df556d1b9641e042c4.png"},{"id":103881096,"identity":"476dd466-2103-4e01-87af-82550a405cee","added_by":"auto","created_at":"2026-03-04 05:25:23","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":46999,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of the methanolic extract on AIP, CRI-I, CRI-II, and AC. Data are presented as mean ± SEM (n = 6). Statistical analysis was performed using two-way ANOVA. d, p ≤ 0.0001 and b, p ≤ 0.01 indicate significant differences compared with the control group; s, p ≤ 0.0001 indicates a significant difference compared with the diabetic control group.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/f27a325aa73b8ad8644ac9f4.png"},{"id":103881100,"identity":"8042e4f9-d830-4802-9248-c1532616b147","added_by":"auto","created_at":"2026-03-04 05:25:23","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":55320,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of the methanolic extract on GSH, LPO, and TP levels. Data are presented as mean ± SEM (n = 6). Statistical analysis was performed using two-way ANOVA. d, p ≤ 0.0001; c, p ≤ 0.001; and e indicates a non-significant change compared with the control group. s, p ≤ 0.0001 indicates a significant difference compared with the diabetic control group.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/d739501106ca8a74a49821cf.png"},{"id":103881092,"identity":"1c6d168d-c96c-4a1b-96b4-7692d9f17bd4","added_by":"auto","created_at":"2026-03-04 05:25:22","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":74805,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of the methanolic extract on the Ferric Reducing Ability of Plasma (FRAP). Data are presented as mean ± SEM (n = 6). Statistical analysis was performed using one-way ANOVA. d, p ≤ 0.0001 compared with the control group; s, p ≤ 0.0001 compared with the diabetic control group.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/8f37c1f0b6744d9125de2e52.png"},{"id":103881093,"identity":"b1115079-223f-4ae1-88c3-5e561a756813","added_by":"auto","created_at":"2026-03-04 05:25:22","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":49758,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of the methanolic extract on insulin levels, β-cell function, and insulin sensitivity. Data are presented as mean ± SEM (n = 6). Statistical analysis was performed using two-way ANOVA. d, p ≤ 0.0001 indicates a significant difference compared with the control group; s, p ≤ 0.0001 indicates a significant difference compared with the diabetic control group.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/8b53bc5dba88046ab7d51525.png"},{"id":103881103,"identity":"5325dd49-91fb-4bb2-bca8-ce7891a3ba67","added_by":"auto","created_at":"2026-03-04 05:25:24","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":49934,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of the methanolic extract on blood glucose and HOMA-IR values. Data are presented as mean ± SEM (n = 6). Statistical analysis was performed using two-way ANOVA. d, p ≤ 0.0001 compared with the control group; s, p ≤ 0.0001 compared with the diabetic control group.\u003c/p\u003e","description":"","filename":"10.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/bb32e8bbfcd781ac49e0957e.png"},{"id":103881097,"identity":"b49f2c3a-40d6-41f7-a018-002403ff4ebc","added_by":"auto","created_at":"2026-03-04 05:25:23","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":850076,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLight microscopic examination of pancreatic tissue (200 X H\u0026amp;E) obtained from various experimental groups. (A)\u003c/strong\u003e Pancreatic histoarchitectures depicted the organized structure consisting of islets of Langerhans, exocrine cells, and blood vessels. \u003cstrong\u003e(B)\u003c/strong\u003e In the diabetic group, Pancreas showing the different degrees of degenerations and vacuolization. \u003cstrong\u003e(C)\u003c/strong\u003eIn the methanolic group, Pancreas showed restoration of histoarchitecture with recovered degenerative tissues in the area of β-cell distribution. \u003cstrong\u003e(D)\u003c/strong\u003e In the sitagliptin group, Pancreas showed organized structure of the islets of Langerhans, and blood vessels.\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/d0c8639c5862fb50038e654c.png"},{"id":104408047,"identity":"1ca87b56-ab05-498d-a112-1cd6f4b04275","added_by":"auto","created_at":"2026-03-11 12:41:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4009779,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/d514db4d-42d3-40a7-80ec-b8a023b112c1.pdf"},{"id":103881104,"identity":"6a1bc5e2-fcfb-487a-84a1-fae7c63553ed","added_by":"auto","created_at":"2026-03-04 05:25:25","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":18439,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfile118.01.2026.docx","url":"https://assets-eu.researchsquare.com/files/rs-8824801/v1/ae22a20336a5efef6070959a.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003e\u003cstrong\u003eMultitargeted antidiabetic intervention of phytocompounds of methanolic fruit extract of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eCordia myxa\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e L.: Integrated from \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003ein-silico \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eand\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003e in-vivo\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e studies\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eConventional food recipes and formulations are selective collections of potent indigenous ingredient which capabilities to interfere in several metabolic pathways and are marked to be therapeutic potential. These ingredients often contain bioactive compounds such as polyphenols, flavonoids, and essential oils, which can be interacting with key enzymes and receptors of metabolism. Accordingly, the unripen fruit of \u003cem\u003eCordia myxa\u003c/em\u003e L. is a key component of the local food recipe of the panchkutta of western Rajasthan, which possesses numerous medicinal properties. Despite its significant nutritional and therapeutic properties, as well as its ability to grow in harsh climatic conditions, it has not gained widespread attention. Traditionally, various parts of the plant have been used in folk medicine to treat a wide range of ailments, including inflammatory conditions, liver diseases, respiratory issues, gastrointestinal disturbances, and metabolic disorders [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Phytochemical profiling of \u003cem\u003eC. myxa\u003c/em\u003e fruits has identified a diverse array of bioactive compounds, including flavonoids, phenolic acids, sterols, terpenoids, saponins, and quinones, many of which have antioxidant, anti-inflammatory, and enzyme-modulating activities [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The abundance of these pharmacologically active compounds suggests that the plant may help regulate blood glucose levels, improve insulin sensitivity, and protect pancreatic β-cells from oxidative damage, making it a promising candidate for antidiabetic therapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlong with this, the ethnopharmacological relevance of \u003cem\u003eC. myxa\u003c/em\u003e, the scientific validation of its antidiabetic activity, and the elucidation of underlying mechanisms remain limited. Some studies suggested that phytocompounds of \u003cem\u003eC. myxa\u003c/em\u003e L. have the potential to inhibit key carbohydrate-metabolizing enzymes, including α-amylase, α-glycosidase, and DPP-4, or to mitigate oxidative stress and improve pancreatic tissue integrity [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Understanding these mechanisms is crucial for translating traditional knowledge into evidence-based therapies. The present study aims to address these gaps by investigating the antidiabetic potential of the methanolic extract of \u003cem\u003eC. myxa\u003c/em\u003e fruits (MECMF). The comprehensive investigation not only provides scientific validation for the traditional use of \u003cem\u003eC. myxa\u003c/em\u003e but also identifies active compounds, elucidates their potential mechanisms, and highlights the plant as a promising natural therapeutic agent for managing type 2 diabetes mellitus.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThe methodology was systemically categorized into three major steps, i.e., phytochemical profiling, \u003cem\u003ein-silico\u003c/em\u003e evaluations, and \u003cem\u003ein-vivo\u003c/em\u003e assessments.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePhytochemical profiling\u003c/h2\u003e \u003cp\u003eChemical profiling was following the collection of plant material, authentication, extraction, and LC–MS/MS analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePlant collection and extract preparation\u003c/h3\u003e\n\u003cp\u003eThe unripe fruit of \u003cem\u003eCordia myxa\u003c/em\u003e (L.) was collected from Chouthpura, Khariberi, Balesar village of Jodhpur. The plant \u003cem\u003eCordia myxa\u003c/em\u003e was identified and authenticated by the Botanical Survey of India (BSI), Jodhpur, Rajasthan, with authentication number \u003cb\u003eBSI/AZRC/I.12012/Tech./2021-22 (PI.Id.)/ 146\u003c/b\u003e. Fruits were shade-dried, coarsely powdered, and extracted with methanol using Soxhlet apparatus for 48 hours [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. The extract was concentrated under reduced pressure, yielding the methanolic extract of \u003cem\u003eC. myxa\u003c/em\u003e fruits (MECMF), which was stored at 4°C until use [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003ePhytochemical analysis\u003c/h3\u003e\n\u003cp\u003eLC–MS/MS data were processed using UNIFI scientific library database. Peaks detected in both positive and negative ionization modes with intensities ≥ 3500 counts were extracted using a peak spacing tolerance of 0.0090 m/z to avoid noise and maintain adequate chromatographic resolution. Molecular masses were assigned based on MS/MS fragmentation patterns characteristic of the identified phytocompounds [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn-silico\u003c/b\u003e \u003cb\u003eassessments\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe identified phytocompounds were docked against α-amylase, α-glycosidase, and DPP-4 to predict their binding affinities and interaction patterns. Pharmacokinetic and toxicity profiles were evaluated using SwissADME and ProTox-III web servers.\u003c/p\u003e\n\u003ch3\u003eRetrieval and preparation of targets and phytocompounds\u003c/h3\u003e\n\u003cp\u003eThe X-crystal structure of Acarbose-bound human pancreatic alpha-amylase (2QV4), alpha glycosidase (2QMJ), and sitagliptin-bound DPP-4 (1X70) were retrieved from the Protein Data Bank (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.rcsb.org/\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and phytocompounds structures are retrieved from the PubChem database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubchem.ncbi.nlm.nih.gov/\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTargeted proteins preparation was done by removing extra chains, water molecules, and bound heteroatoms. After that, polar hydrogen, Kollman charges were added, and assigned charges [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. Ligand preparation entailed adding polar hydrogen assigned Gasteiger charges, and energy is minimized using the Avogadro tool[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eMolecular docking analysis\u003c/h3\u003e\n\u003cp\u003eDocking simulations were performed using AutoDock 4.2 to assess the molecular interaction between targets and phytoconstituents [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. The grid boxes were centered on the active site coordinates of the native co-crystallized ligands: X = 12.942, Y = 47.169, Z = 26.2 Å, X = -19.6, Y= -6.86, Z= -9.68 Å, and X = 41.18, Y = 51.04, Z = 35.62 Å for prepared α-amylase, α-glycosidase, and DPP-4, respectively, with a spacing of 0.375 Å. Docking accuracy was validated by redocking native ligands, achieving RMSD \u0026lt; 2 Å. Acarbose and sitagliptin served as standard inhibitors for α-amylase/α-glycosidaseand DPP-4, respectively [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. Docked complexes were analyzed for binding affinity and interactions using Discovery Studio tools.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eADME and toxicity prediction\u003c/h2\u003e \u003cp\u003eADME analysis was carried out using SwissADME (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.swissadme.ch/index.php\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to predict molecular weight, lipophilicity (iLogP, CLogP), hydrogen-bond donors/acceptors, topological polar surface area (TPSA), gastrointestinal absorption, and blood–brain barrier (BBB) permeability [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eToxicological profiles were assessed using the \u003cem\u003ein silico\u003c/em\u003e Protox-III web server (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://tox.charite.de/protox3/\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The predictions included: Hepatotoxicity, nephrotoxicity, carcinogenicity, respiratory, mutagenicity, LD50 to evaluate the level of acute toxicity, and toxicity classes were assigned following Globally Harmonized System of Classification and Labelling of Chemicals (GHS) guidelines [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. This predictive approach enhances the early-stage evaluation of chemical safety, aiding in the identification of promising drug candidates with minimal toxicity risks.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDynamics simulation\u003c/h3\u003e\n\u003cp\u003eMD simulations were performed using the SiBioLead web platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://sibiolead.com/\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), which operates on a GROMACS-based backend. Each protein–ligand complex was parameterized with the OPLS/AA force field and solvated in an SPC water model within a dodecahedral box. The system was neutralized with Na⁺/Cl⁻ ions and adjusted to 0.15 mM ionic strength. Energy minimization was conducted using the steepest descent algorithm for 5000 steps, followed by NVT and NPT equilibration at 300 K and 1 bar for 100 ps. A 1 ns production run was performed using the MD integrator. The resulting XVG trajectories were used to extract RMSD and hydrogen-bond profiles, and mean ± SD values were calculated in Excel.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn-vivo\u003c/b\u003e \u003cb\u003eassessment\u003c/b\u003e\u003c/p\u003e\n\u003ch3\u003eDevelopment of the type 2 diabetes mellitus animal model\u003c/h3\u003e\n\u003cp\u003eAnimal model (weight 180–225 gm) was developed through the chemical induction method by following the use of nicotinamide and streptozotocin. Healthy adult male rats were treated with nicotinamide (200mg/kg) through intraperitoneal dispersal with 0.9% sodium chloride. Pretreated nicotinamide rats were used for the intraperitoneal administration of streptozotocin (60mg/kg) by dissolving it into sodium citrate buffer (4.5 PH), following the standard protocol through estimation of OGTT (Oral Glucose Tolerance Test). After 48 hours, by examining fasting glucose \u0026gt; 250 mg/dl confirmed diabetic induction [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eDesign of experimental protocol\u003c/h2\u003e \u003cp\u003eThe experiment protocol was approved by the Institutional Ethical Committee (IAEC), Department of Zoology, Jai Narain Vyas University, Jodhpur (Rajasthan), India (\u003cb\u003e1646/GO/Ere/S/12/CCSEA\u003c/b\u003e). The animals were kept in spacious cages with a 12-hour light and 12-hour night cycle with 20–25°C temperature and 50–60% relative humidity. Standard rodent pellets and water were given in ad libitum[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]. The whole experiment was divided into four groups, consisting of six animals in each group, for the experimentation course of 28 days (four weeks) [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. The extract was given orally (300 mg/kg Body Weight) with the help of an oral feeding cannula (18g ball tip curved), and doses were assessed by LD\u003csub\u003e50\u003c/sub\u003e values.\u003c/p\u003e \u003cp\u003eGroup I: Intact control or vehicle control (non-diabetic)\u003c/p\u003e \u003cp\u003eGroup II: Type 2 Diabetes mellitus control (diabetic).\u003c/p\u003e \u003cp\u003eGroup III: Diabetic + Sitagliptin (10 mg/kg Body Weight)\u003c/p\u003e \u003cp\u003eGroup IV: Diabetic + Methanol extract of \u003cem\u003eC. myxa\u003c/em\u003e fruit (300 mg/kg Body Weight)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAssessments of serum biochemical parameters\u003c/h2\u003e \u003cp\u003eAfter a 28-day experimental period, the rats, having undergone an overnight fast, were humanely euthanized using mild anesthesia. Blood samples were drawn from both the retro-orbital plexus and via cardiac puncture. The collected blood was centrifuged at 3000 rpm for 15 minutes to separate the serum, which was then stored at − 20°C for subsequent biochemical analysis [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. Various serum-based assays were performed to evaluate glucose metabolism, including measurements of glucose and insulin levels, as well as lipid profile parameters. Additionally, oxidative stress markers—such as glutathione (GSH), superoxide dismutase (SOD), catalase, lipid peroxidation (LPO), and ferric reducing antioxidant power (FRAP)—were analyzed in relation to total protein content [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. Quantitative estimations of glucose, total protein (TP), and lipid profile (total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL)) were carried out using commercial enzymatic kits provided by ERBA Diagnostic Pvt. Ltd.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eEstimation of HOMA IR, HOMA-\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\varvec{\\beta\\:}\\)\u003c/span\u003e\u003c/span\u003e, and Quiki\u003c/h2\u003e \u003cp\u003eThe quantification of insulin resistance and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\beta\\:\\)\u003c/span\u003e\u003c/span\u003e-cell functioning was done by using the HOMA (Homeostatic Model Assessment) method. HOMA-IR (Insulin resistance), HOMA-\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\beta\\:\\)\u003c/span\u003e\u003c/span\u003e (beta cell-function, and QUICKI (quantitative insulin sensitivity check index) are valid estimations for insulin sensitivity in patients with type 2 diabetes [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:\\text{H}\\text{O}\\text{M}\\text{A}-\\beta\\:\\:\\left(\\text{%}\\right)=\\frac{20\\times\\:\\text{F}\\text{a}\\text{s}\\text{t}\\text{i}\\text{n}\\text{g}\\:\\text{i}\\text{n}\\text{s}\\text{u}\\text{l}\\text{i}\\text{n}\\:({\\mu\\:}\\text{U}/\\text{m}\\text{L})}{\\text{F}\\text{a}\\text{s}\\text{t}\\text{i}\\text{n}\\text{g}\\:\\text{g}\\text{l}\\text{u}\\text{c}\\text{o}\\text{s}\\text{e}\\:\\left(\\frac{\\text{m}\\text{m}\\text{o}\\text{l}}{\\text{L}}\\right)-3.5}$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\u003cdiv class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n$$\\:\\text{H}\\text{O}\\text{M}\\text{A}-\\text{I}\\text{R}=\\frac{\\text{F}\\text{a}\\text{s}\\text{t}\\text{i}\\text{n}\\text{g}\\:\\text{i}\\text{n}\\text{s}\\text{u}\\text{l}\\text{i}\\text{n}\\:\\left(\\frac{{\\mu\\:}\\text{U}}{\\text{m}\\text{L}}\\right)\\times\\:\\text{F}\\text{a}\\text{s}\\text{t}\\text{i}\\text{n}\\text{g}\\:\\text{g}\\text{l}\\text{u}\\text{c}\\text{o}\\text{s}\\text{e}\\:(\\text{m}\\text{m}\\text{o}\\text{l}/\\text{L})}{22.5}$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equc\" class=\"Equation\"\u003e\u003cdiv class=\"mathdisplay\" id=\"FileID_Equc\" name=\"EquationSource\"\u003e\n$$\\:\\text{H}\\text{O}\\text{M}\\text{A}\\:\\text{S}\\text{%}=\\frac{1}{\\text{H}\\text{O}\\text{M}\\text{A}-\\text{I}\\text{R}}\\times\\:100$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equd\" class=\"Equation\"\u003e\u003cdiv class=\"mathdisplay\" id=\"FileID_Equd\" name=\"EquationSource\"\u003e\n$$\\:\\text{Q}\\text{U}\\text{I}\\text{C}\\text{K}\\text{I}=\\frac{1}{{\\text{L}\\text{o}\\text{g}}_{10}(\\text{F}\\text{a}\\text{s}\\text{t}\\text{i}\\text{n}\\text{g}\\:\\text{i}\\text{n}\\text{s}\\text{u}\\text{l}\\text{i}\\text{n}\\:\\left({\\mu\\:}\\text{U}/\\text{m}\\text{L})\\right)+{\\text{L}\\text{o}\\text{g}}_{10}(\\text{F}\\text{a}\\text{s}\\text{t}\\text{i}\\text{n}\\text{g}\\:\\text{g}\\text{l}\\text{u}\\text{c}\\text{o}\\text{s}\\text{e}\\:\\left(\\frac{\\text{m}\\text{g}}{\\text{d}\\text{L}}\\right))}$$\u003c/div\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eHistology of pancreas\u003c/h2\u003e \u003cp\u003ePancreatic tissues were collected from necropsied rats, washed with phosphate-buffered saline, and fixed in 10% neutral buffered formalin for 24 h. After washing, samples were dehydrated through graded ethanol (30–100%), cleared in xylene, and embedded in paraffin wax at 55–60°C. Sections of 5 µm thickness were prepared using a rotary microtome, stained with hematoxylin and eosin, following standard procedures [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e], and mounted with DPX. The slides were examined under a phase-contrast microscope (Nikon Research Microscope System, Germany), and representative photomicrographs were captured at 200× magnification.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe biochemical and antioxidant parameters were expressed in terms of mean ±standard error mean[\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]. Statistical analysis was performed using two-way and one-way analysis of variance (ANOVA), followed by Tukey’s test to evaluate the statistical differences between the means of the various groups. A p-value ≤ 0.05 was considered significant. Statistical analyses and graphical representations were conducted using GraphPad Prism-7 software, and Histological photographs were analyzed using ImageJ software.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003ch2\u003eIdentification of phytoconstituents through LC-MS/MS\u003c/h2\u003e\u003cp\u003eLC–MS profiling of the test extract revealed the occurrences of twelve leading phytoconstituents (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e \u0026amp; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA-B). The identified compounds included polyphenols (ferulic acid, caffeic acid, and rosmarinic acid), flavonoids (catechin and rutin), triterpenoids (α-amyrin), sterols (β-sitosterol), and fatty alcohols/acids (octacosanol and oleic acid). Importantly, \u003cem\u003eCordia\u003c/em\u003e-specific metabolites Cordiaquinone C and Cordiaquinone G were identified at retention times of 1.77 min and 9.27 min. The detected compounds spanned retention times from 1.60 to 24.74 min with corresponding m/z values consistent with their molecular weights.\u003c/p\u003e\u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab1\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIdentified masses from UPLC-QTOF mass spectroscopy constituents in the \u003cem\u003eC. myxa\u003c/em\u003e methanolic extract in negative and positive electron ionization mode\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003eS.No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eIdentified compound Name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eFormula\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eMonoisotopic mass (g/mol)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eRetention time (min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003em-z/ m + z values\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFerulic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e10\u003c/sub\u003eH\u003csub\u003e10\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e194.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.93 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e217.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e2.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAlpha-amyrin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e30\u003c/sub\u003eH\u003csub\u003e50\u003c/sub\u003eO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e426.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e24.74 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e426.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e3.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOctacosanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e58\u003c/sub\u003eO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e410.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.60 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e387.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e4.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCaffeic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e9\u003c/sub\u003eH\u003csub\u003e8\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e180.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.77 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e157.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e5.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eβ- sitosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e50\u003c/sub\u003eO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e414.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.77 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e391.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e6.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e26\u003c/sub\u003eH\u003csub\u003e30\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e406.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.77 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e383.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e7.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCatechin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e15\u003c/sub\u003eH\u003csub\u003e14\u003c/sub\u003eO\u003csub\u003e6\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e290.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.98 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e289.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e8.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOleic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e34\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e282.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.98 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e259.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e9.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSyringaldehyde\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e9\u003c/sub\u003eH\u003csub\u003e10\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e182.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e5.10 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e181.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e10.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRosmarinic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e16\u003c/sub\u003eO\u003csub\u003e8\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e360.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e8.38 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e359.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e11.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e342.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e9.27 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e343.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e12.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRutin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eC\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e30\u003c/sub\u003eO\u003csub\u003e16\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e610.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e24.35 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e587.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003cb\u003eIn-silico\u003c/b\u003e \u003cb\u003eanalysis\u003c/b\u003e\u003c/p\u003e\u003ch2\u003eMolecular docking through Autodock4\u003c/h2\u003e\u003cp\u003eThe re-docking validation revealed that Alpha-amylase, Alpha glycosidase, and DPP4 re-docked native ligand exhibited an RSMD value of 1.2Å, 0.7 Å, 0.5 Å, and with a binding energy of -11.7, -8.61, -8 Kcal/mol, respectively (Supplementary file 1). Docking investigations identified three bioactive constituents from \u003cem\u003eCordia myxa\u003c/em\u003e exhibiting notable affinity toward carbohydrate-metabolizing enzymes. Cordiaquinone-C displayed a binding energy of -9.92 kcal mol⁻¹ with α-amylase, approaching the reference inhibitor Acarbose (-11.7 kcal mol⁻¹). Cordiaquinone-G bound effectively with α-glycosidase (-8.75 kcal mol⁻¹), slightly exceeding the affinity of Acarbose (-8.61 kcal mol⁻¹). Likewise, β-sitosterol showed a binding score of -9.32 kcal mol⁻¹ against DPP-IV, surpassing the standard compound (-8.0 kcal mol⁻¹). These findings indicate a strong potential of the identified compounds to interact with their respective enzymatic targets. The interaction profiles, including hydrogen bonds and hydrophobic contacts, were visualized using Discovery Studio Visualizer, confirming stable and well-oriented binding within the catalytic pockets of the enzymes (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e–\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA-F). Consequently, the α-amylase–Cordiaquinone-C, α-glycosidase–Cordiaquinone-G, and DPP-IV–β-sitosterol complexes were selected for molecular dynamics simulations to further assess their structural stability, binding persistence, and conformational dynamics under standard parameters.\u003c/p\u003e\u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab2\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe binding energies obtained with identified phytocompounds along with interacting residues and bond length of molecular interaction of methanolic extract with α-amylase (2QV4)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003ePhytoconstituents\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eα-amylase (binding energy)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eInteracting Residues\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eBond types\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eDistance\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAlpha-amyrin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-9.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTyr62, Trp59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003ePi-Sigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e3.93, 4.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFerulic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-4.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTyr151, Asp197, Lys200, \u003c/p\u003e \u003cp\u003eHis101, Leu162, Ala198, Glu233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Alkyl, \u003c/p\u003e \u003cp\u003ePi-Anion, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.02, 1.93, 1.86, 4.54, 4.87, 5.10, 3.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOctacosanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-3.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTyr62, Trp58, Trp59, Leu165,\u003c/p\u003e \u003cp\u003eLys200, His201, Ile235, His305\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003ePi-Sigma, Pi-Alkyl, \u003c/p\u003e \u003cp\u003eAlkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e3.43, 5.32, 5.26, 5.41, 4.74, 4.92, 5.36, 5.22, 4.12, 4.42, 3.98, 5.19, 4.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCaffeic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-4.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTyr151, Asp197, Lys200, \u003c/p\u003e \u003cp\u003eAla198, Glu233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl,\u003c/p\u003e \u003cp\u003ePi-Anion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.06, 1.90, 1.90, 1.84, 5.01, 3.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-9.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eGln63, His201, Leu165, \u003c/p\u003e \u003cp\u003eLys200, Ile235, Glu233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Alkyl, CH-bond,\u003c/p\u003e \u003cp\u003ePi-Alkyl, Pi-Sigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.84, 2.23, 5.02, 3.58, 5.16, 4.12,\u003c/p\u003e \u003cp\u003e4.87, 3.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSyringaldehyde\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-4.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTyr151, Ile235, Lys200,\u003c/p\u003e \u003cp\u003eLeu162, His201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Pi T-shaped, \u003c/p\u003e \u003cp\u003ePi-Cation, Alkyl,\u003c/p\u003e \u003cp\u003ePi-Sigma, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.13, 3.89, 1.74, 3.75, 2.40, 5.16, 5.39, 4.64, 2.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRosmarinic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-6.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eHis15, Val42, Arg337, Ser43, Arg195,\u003c/p\u003e \u003cp\u003eGln41, Tyr62, Asp96, Asn298, His299\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Van der Waals,\u003c/p\u003e \u003cp\u003ePi-Sulfur, Unfavourable Bump,\u003c/p\u003e \u003cp\u003ePi-Lone Pair, Amide-Pi Stacked,\u003c/p\u003e \u003cp\u003eCH-bond, Pi-Alkyl, Pi-Cation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.78, 2.59, 2.83, 2.00, 3.04, 2.47, 5.21, 2.29, 1.42, 6.30, 2.02, 2.47,\u003c/p\u003e \u003cp\u003e2.18, 2.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eBeta-sitosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-9.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAsp300, Trp58, Trp59, Tyr62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.06, 5.38, 4.10, 4.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCatechin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-6.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eGln63, Tyr62, Asp197, \u003c/p\u003e \u003cp\u003eGlu233, Trp59, Ala198\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Anion, \u003c/p\u003e \u003cp\u003eUnfavourable Doner-Doner,\u003c/p\u003e \u003cp\u003ePi-Pi Stacked\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.98, 1.82, 4.43, 2.00, 2.47, 4.50,\u003c/p\u003e \u003cp\u003e2.13, 2.50, 4.82, 2.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-8.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLys200, Asp300, Ile235, Leu162,\u003c/p\u003e \u003cp\u003eAla198, His201, Glu233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Sigma, \u003c/p\u003e \u003cp\u003eUnfavourable Acceptor-Acceptor,\u003c/p\u003e \u003cp\u003ePi-Pi T-shaped, Pi-Cation,\u003c/p\u003e \u003cp\u003ePi-Alkyl, Pi-Anion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.50, 4.50, 1.94, 2.05, 3.61, 5.40,\u003c/p\u003e \u003cp\u003e4.99, 4.83, 3.34, 4.07, 2.97, 4.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOleic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-4.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLys200, Trp59, Tyr62, Leu162,\u003c/p\u003e \u003cp\u003eLeu165, Ala198, His201, Ile235\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl, Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.20, 4.93, 3.90, 5.46, 4.88, 5.35, 4.36, 5.28, 5.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRutin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-7.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTy62, Gln63, Arg195, Asp197, Glu233, \u003c/p\u003e \u003cp\u003eAsp300, His305, Gly306, Leu165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl, CH-bond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.83, 2.01, 1.85, 2.18, 1.66, 2.03,\u003c/p\u003e \u003cp\u003e2.46, 2.12, 2.56,1.80, 1.89, 2.00,\u003c/p\u003e \u003cp\u003e3.45, 5.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab3\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe binding energies obtained with identified phytocompounds along with interacting residues and bond length of molecular interaction of methanolic extract with α-glycosidase (2QMJ)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003ePhytoconstituents\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eα-glycosidase (binding energy)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eInteracting Residues\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eBond types\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eDistance\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAlpha-amyrin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-6.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTyr605, Phe450\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Sigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.93, 3.43, 3.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFerulic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-3.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eGln603, Tyr605\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.93, 2.09, 4.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOctacosanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-2.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTrp539, Asp542, Phe575, Tyr299, \u003c/p\u003e \u003cp\u003eTrp406, Phe450, Lys480, His600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Sigma, Alkyl, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.81, 1.83, 3.95, 4.99, 5.10,\u003c/p\u003e \u003cp\u003e 4.04, 5.09, 4.98, 5.50, 4.35,\u003c/p\u003e \u003cp\u003e4.19, 4.04, 4.77, 5.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCaffeic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-3.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAsp203, Asp327, Arg526, His600, Tyr299, Asp443, Met444\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Anion,\u003c/p\u003e \u003cp\u003eSulfur-X, Pi-Pi T-shaped\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.74, 1.72, 1.61, 2.18, 1.85,\u003c/p\u003e \u003cp\u003e5.73, 3.47, 3.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-7.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eArg202, Asp203, Ile328, Ile364, \u003c/p\u003e \u003cp\u003eTrp406, Lys480\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Alkyl, Pi-Anion, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4.89, 3.17, 3.59, 4.20, 5.06,\u003c/p\u003e \u003cp\u003e5.15, 4.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSyringaldehyde\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-5.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eArg526, Asp542, Asp327, Asp443,\u003c/p\u003e \u003cp\u003eMet444, Trp539, Phe575, His600,\u003c/p\u003e \u003cp\u003eAsp571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Alkyl, CH-bond, Pi-Alkyl,\u003c/p\u003e \u003cp\u003ePi-Anion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.10, 2.10, 2.10, 3.16, 3.10,\u003c/p\u003e \u003cp\u003e2.99, 3.23, 5.21, 5.69, 4.07,\u003c/p\u003e \u003cp\u003e3.97, 3.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRosmarinic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-7.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAsp203, Asp327, Arg334, Trp406,\u003c/p\u003e \u003cp\u003e Asp443, Arg526, Tyr605, Phe450\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Pi T-shaped, Pi-Pi Stacked\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.84, 2.01, 1.87, 1.83, 2.19, 4.50, 1.61, 1.72, 2.85, 2.10, 2.26, 5.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eBeta-sitosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-7.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTyr299, Trp406, Trp441, Met444,\u003c/p\u003e \u003cp\u003e Trp539, Phe575, His600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003ePi-Sigma, Pi-Alkyl, Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e3.64, 5.07, 5.18, 4.96, 5.67,\u003c/p\u003e \u003cp\u003e4.88, 4.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCatechin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-6.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAsp443, Arg526, Asp542, Gln603, Tyr299, Trp406\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Doner H-bond, Pi-Anion,\u003c/p\u003e \u003cp\u003ePi-Pi T-shaped\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.85, 1.77, 1.85, 4.49, 1.70, 1.83, 3.03, 5.50, 4.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-8.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAsp327, Asp542, His600, Tyr299, \u003c/p\u003e \u003cp\u003eGly602\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-PI T-shaped, CH-bond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.72, 2.23, 1.78, 4.69, 5.21, 3.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOleic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eArg334, Gln603, Tyr605, Phe575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.01, 1.90, 2.18, 1.99, 4.57, 4.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRutin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-8.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAsp203, Asp327, Arg334, Trp406, Asp443, Asp542, His600, Tyr605, Phe450\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Pi T-shaped, Pi-Pi Stacked\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.16, 1.74, 1.92, 1.86, 2.53, 2.26, 2.36, 2.06, 2.10, 2.28, 5.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab4\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe binding energies obtained with identified phytocompounds along with interacting residues and bond length of molecular interaction of methanolic extract with DPP-4 (1X70)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003ePhytoconstituents\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eDPP-4 (binding Energy)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eInteracting Residues \u003c/p\u003e \u003cp\u003ewith DPP-4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eBond types\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eDistance\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAlpha-amyrin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-7.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTyr547, Arg358\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.90, 5.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFerulic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-4.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eGlu206, Val207, Arg358, Arg669, Ser209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Lone Pair, CH-bond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.90, 2.75, 2.11, 1.94, 1.89,\u003c/p\u003e \u003cp\u003e3.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOctacosanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-2.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eVal207, Phe357, Tyr547, Tyr662,\u003c/p\u003e \u003cp\u003eTyr666, Val711, His740\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Alkyl, Pi-Sigma, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.03, 5.01, 5.20, 4.82, 5.43,\u003c/p\u003e \u003cp\u003e3.50, 4.35, 5.37, 4.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCaffeic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-5.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eVal207, Glu206, Arg358, Arg669, Phe357\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Pi Stacked, Unfavourable \u003c/p\u003e \u003cp\u003eAcceptor-Acceptor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.96, 1.86, 1.98, 2.83, 3.69,\u003c/p\u003e \u003cp\u003e2.40, 4.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-8.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTyr547, Arg358, Tyr631, Val656, Trp659, Tyr662, Tyr666, Ser630\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Alkyl, CH-bond, Pi-Alkyl,\u003c/p\u003e \u003cp\u003ePi-Sigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.87, 4.97, 5.29, 4.68, 4.49, 3.77, 3.94, 3.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSyringaldehyde\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-4.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eArg125, Glu205, Ser630, Tyr547, Tyr666, Glu206\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl, CH-bond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.33, 2.25, 2.43, 5.08, 4.60, 2.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRosmarinic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-7.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eArg125, Glu206, Ser630, Arg669 Tyr666, Phe357, Tyr662, His740\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Pi Stacked, CH-bond, \u003c/p\u003e \u003cp\u003ePi-Pi T-shaped, Unfavourable Doner-Doner\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.99, 2.87, 1.67, 2.20, 2.09, 2.00, 6.14, 2.15, 5.22, 5.04, 4.54, 3.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eBeta-sitosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-9.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003ePhe357, Tyr662, Tyr666, Arg358\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eUnfavourable Doner-Doner, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4.99, 5.15, 5.10, 4.74, 5.47, 1.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCatechin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-7.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eGlu205, Phe357, Ser630, \u003c/p\u003e \u003cp\u003eTyr662, Tyr666, Tyr631\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl, Pi-Pi T-shaped,\u003c/p\u003e \u003cp\u003eAmide-Pi Stacked, Pi-Pi Stacked, \u003c/p\u003e \u003cp\u003evan der Waals\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.05, 2.12, 4.99, 4.51, 4.48, 5.63, 4.78, 5.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-6.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eGlu205, Asn710, Arg358, Tyr666\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Sigma, CH-bond, Pi-Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.14, 3.05, 3.07, 5.38, 3.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOleic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-3.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eArg358, Phe357, Tyr631, Val656,\u003c/p\u003e \u003cp\u003eTrp659, Tyr662, Tyr666, His740\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl, Alkyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.65, 2.73, 4.71, 5.14, 5.35, 5.23, 5.38, 4.11, 4.31, 5.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRutin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-6.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eGlu206, Phe357, Arg358, Tyr547,\u003c/p\u003e \u003cp\u003eCys551, Tyr585, Tyr666, Arg669,\u003c/p\u003e \u003cp\u003eGlu205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eH-bond, Pi-Alkyl, CH-bond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.75, 2.34, 2.08, 2.63, 5.00, 2.18, 2.84, 2.03, 2.47, 2.42, 6.14, 3.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e\u003ch2\u003eADME and toxicity prediction\u003c/h2\u003e\u003cp\u003eAccording to the ADME study, the derivatives Alpha-amyrin, Cordiaquinone C, and Cordiaquinone G, which exhibited favorable binding affinities with the target proteins, adhered to the Lipinski Rule of Five with no violations. Beta-sitosterol exhibited favorable binding affinities with the target proteins, adhered to the Lipinski Rule of Five with 1 violation. These \u003cem\u003eCordia-specific\u003c/em\u003e quinones show high intestinal absorption and cross the BBB as per BOILED-Egg prediction (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Results of ADME analysis are tabulated in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e. The toxicity prediction of the alpha amyrin exhibited nephron toxicity and respiratory toxicity. Cordiaquinone C and Cordiaquinone G show respiratory toxicity. Beta-sitosterol shows neurotoxicity alerts (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab5\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMolecular Weight, Lipophilicity, Hydrogen Bonding Features, TPSA, GI/BBB Predictions, and Lipinski Compliance of the Selected Compounds using SwissADME web server\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eMW\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eiLogP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eCLogP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eHBA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eHBD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eTPSA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eGI/BBB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eLipinski rule\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAlpha-amyrin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e426.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e7.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e20.23 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLow \u0026amp; No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 0 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFerulic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e194.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e66.76 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eHigh \u0026amp; Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 0 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOctacosanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e410.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e7.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e20.23 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLow \u0026amp; No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 1 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCaffeic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e180.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e77.76 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eHigh \u0026amp; No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 0 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e406.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e3.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e60.44 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eHigh \u0026amp; Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 0 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSyringaldehyde\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e182.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e55.76 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eHigh \u0026amp; Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 0 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRosmarinic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e360.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e144.52 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLow \u0026amp; No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 0 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eBeta-sitosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e414.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e7.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e20.23 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLow \u0026amp; No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 1 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCatechin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e290.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e110.38 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eHigh \u0026amp; No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 0 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e342.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e74.6 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eHigh \u0026amp; Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 0 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOleic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e282.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e37.3 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eHigh \u0026amp;No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 1 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRutin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e610.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e269.43 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLow \u0026amp; No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo, 3 violations\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAcarbose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e807.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e-0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e400.32 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLow \u0026amp; No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo, 3 violations\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSitagliptin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e407.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e77.04 Å\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eHigh \u0026amp; Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes, 0 violation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab6\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePredicted Toxicological Profiles of the Selected Compounds by Protox 3.0 web tool.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003ePhytoconstituents\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eHepato-\u003c/p\u003e \u003cp\u003eToxicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eNeuro-\u003c/p\u003e \u003cp\u003eToxicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eNephro-\u003c/p\u003e \u003cp\u003eToxicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eCarcino-\u003c/p\u003e \u003cp\u003eToxicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eResp-\u003c/p\u003e \u003cp\u003eToxicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eMuta-\u003c/p\u003e \u003cp\u003eToxicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eLD50 \u003c/p\u003e \u003cp\u003e(mg/kg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eToxicity \u003c/p\u003e \u003cp\u003eclass\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAlpha-amyrin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFerulic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1772\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOctacosanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCaffeic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2980\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSyringaldehyde\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRosmarinic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eBeta-sitosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e890\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCatechin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e10000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eCordiaquinone G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eOleic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRutin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSitagliptin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAcarbose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eActive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e\u003ch2\u003eDynamics simulation\u003c/h2\u003e\u003cp\u003eThe backbone RMSD plots (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA–C) indicate that all protein–ligand complexes rapidly achieved structural equilibrium and remained stable throughout the 1-ns simulation. Likewise, the hydrogen-bond profiles (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eD–F) reveal persistent and well-defined polar interactions across the trajectory. The combination of early RMSD convergence and consistent hydrogen-bonding patterns confirms that the complexes attained a stable binding state, thereby supporting the reliability of the 1-ns MD results and validating the structural interpretations drawn from this timeframe.\u003c/p\u003e\u003ch2\u003eStructural stability assessed by RMSD\u003c/h2\u003e\u003ch2\u003eα-Amylase complexes\u003c/h2\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA, Acarbose displayed a smooth and tightly clustered RMSD trajectory (µ = 0.1128 ± 0.0077 nm), reflecting a stable binding mode with minimal structural perturbation. Cordiaquinone C showed slightly higher fluctuations (µ = 0.1244 ± 0.0118 nm) yet remained within the acceptable range for stable complexes (\u0026lt; 0.20 nm). The marginally elevated RMSD variance of cordiaquinone C suggests increased local flexibility but not destabilization of the protein fold.\u003c/p\u003e\u003ch2\u003eα-glycosidase complexes\u003c/h2\u003e\u003cp\u003eIn Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eB, Acarbose again exhibited consistent stability (µ = 0.1266 ± 0.0074 nm). Cordiaquinone G demonstrated comparable stability with an RMSD mean of 0.1244 ± 0.0118 nm, indicating that the ligand adopted a stable conformation without inducing backbone deviation. The close similarity between the two ligands reflects robust accommodation within the α-glycosidase catalytic cleft.\u003c/p\u003e\u003ch2\u003eDPP-4 complexes\u003c/h2\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eC, sitagliptin exhibited moderate fluctuations (µ = 0.1372 ± 0.0165 nm) but stabilized early and remained steady thereafter. β-Sitosterol showed a slightly higher RMSD (µ = 0.1420 ± 0.0204 nm), which is expected given its bulky hydrophobic structure. Nevertheless, its RMSD stability indicates effective retention within the DPP-4 binding pocket.\u003c/p\u003e\u003ch2\u003eHydrogen bond analysis\u003c/h2\u003e\u003ch2\u003eα-Amylase complexes\u003c/h2\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eD, Acarbose formed recurrent hydrogen bonds, frequently maintaining 1–4 simultaneous interactions with an average of 1.16 ± 0.94. Cordiaquinone C, however, showed sparse and short-lived hydrogen bonding (0.21 ± 0.46), indicating that its stabilization relies more on hydrophobic or aromatic interactions rather than persistent polar contacts. Despite lower H-bond occupancy, the RMSD stability suggests that cordiaquinone C remains well anchored within the active site.\u003c/p\u003e\u003ch2\u003eα-glycosidase complexes\u003c/h2\u003e\u003cp\u003eIn Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eE, Acarbose again displayed strong hydrogen bonding (µ = 1.31 ± 0.76), consistent with its polar nature. Cordiaquinone G exhibited moderate hydrogen bonding (µ = 0.99 ± 0.70) that occurred intermittently but remained dynamically relevant. The stable RMSD and moderate H-bonding indicate a balance of hydrophobic and polar contacts in Cordiaquinone G enzyme interactions.\u003c/p\u003e\u003ch2\u003eDPP-4 complexes\u003c/h2\u003e\u003cp\u003eHydrogen bonding in DPP-4 was minimal for both ligands (β-Sitosterol and sitagliptin) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eF). Sitagliptin exhibited very low mean H-bond occupancy (0.028 ± 0.164), consistent with its pharmacophore design, where hydrophobic and π-stacking interactions dominate protein engagement. β-Sitosterol, being structurally hydrophobic, showed slightly higher but still low H-bonding (0.086 ± 0.280). Despite minimal polar interactions, both complexes remained structurally stable, reflecting the hydrophobic nature of the DPP-4 binding cleft.\u003c/p\u003e\u003cp\u003e \u003cb\u003eIn-vivo\u003c/b\u003e \u003cb\u003eassessments\u003c/b\u003e\u003c/p\u003e\u003ch2\u003eBiochemical parameters assessments\u003c/h2\u003e\u003ch2\u003eLipid profiling and dyslipidemia indices\u003c/h2\u003e\u003cp\u003eThe treatment produced a marked improvement in the lipid profile of diabetic rats (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Triglyceride (TG) and total cholesterol (TC) concentrations were significantly reduced in the treated group compared with the diabetic control, accompanied by a clear decline in LDL and VLDL levels. Although HDL levels showed only marginal and statistically non-significant changes, the overall lipid-modulating effect was evident, reflecting the treatment’s potential to counteract diabetes-induced dyslipidemia. Consistently, the atherogenic indices AIP (Atherogenic Index of Plasma), CRI-I, CRI-II (Castelli Risk Index I \u0026amp; II), and AC (Atherogenic Coefficient) were significantly lowered following treatment, indicating enhanced lipid homeostasis and a diminished risk of diabetes-related cardiovascular complications (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003ch2\u003eAntioxidants\u003c/h2\u003e\u003cp\u003eThe treated group exhibited a significant elevation in GSH and FRAP levels compared to the diabetic control, indicating improved antioxidant status. Total protein (TP) levels showed non-significant variation among the groups, while LPO levels were markedly reduced in the treated group, suggesting attenuation of lipid peroxidation. The results of the treated group reflect enhanced oxidative defense and renal protection relative to the diabetic group (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e–\u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003ch2\u003eHOMA indices\u003c/h2\u003e\u003cp\u003eHOMA indices evaluation shows that insulin levels, β-cell function (HOMA-β), and insulin sensitivity (QUICKI) declined in the diabetic group compared to the control group, whereas the treatment group and sitagliptin reduced insulin resistance significantly. Additionally, the treated and standard group showed notable improvement in blood glucose regulation and insulin resistance (HOMA-IR), demonstrating better glycemic control (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e9\u003c/span\u003e–\u003cspan class=\"InternalRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e \u003cb\u003e3.3.2 Histology\u003c/b\u003e \u003c/p\u003e\u003cp\u003eCompact and organized histoarchitecture of the pancreases were composed of islets of the Langerhans, exocrine cells, blood vessels, and connective tissues in the vehicle control group. Each islet is situated in a cellular plate with anastomosing connections. In the diabetic group, the pancreas showed vacuolations with different degrees of degeneration in the cellular content of the islet. Whereas, the treatments of the test extract and sitagliptin caused significant ameliorations in cellular mass by subsiding the vacuolations and diminishing the degenerative changes (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHerbal extracts are assemblages of the potent phytocompounds that work synchronically or independently with specific targets or concerned combined characteristics to support the therapeutics[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Subsequently, the phytochemical profiling of the test extract shown existence of potent phytocompounds with different patterns and features, including phenolic acids, flavonoids, sterols, terpenoids, and the characteristic quinones Cordiaquinone C and Cordiaquinone G, each of which is known for its biological relevance in oxidative balance and metabolic regulation, as depicted by the previous studies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. This broad chemical profile points toward a multifaceted mode of action rather than reliance on a single dominant compound.\u003c/p\u003e \u003cp\u003eAccordingly, the mode of action of small-molecule phytocompounds depends on the interaction capabilities with active sites and the stabilities of the complexes, which resulted in the biological activities[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The molecular docking showed that the key constituents of the extract interact compatibly with α-amylase, α-glycosidase, and DPP-4, displaying through binding energies, numbers of hydrogen bonds, and bond lengths. These interactions were executed by hydrophobic interactions, aromatic stacking, and selective hydrogen bonding within the catalytic regions of the enzymes[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The interactions were further validated through key molecular dynamic simulation parameters such as RSMD and consistency of hydrogen bonding status. RMSD (Root-Mean-Square Deviation) is a basic calculation that calculates the average distance between the atoms of a superimposed protein or molecule in different conformations [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Accordingly, the interpretations of the RSMD of three complexes validate the interaction capabilities. The values of RSMD of complexes were confirmed by the status of hydrogen bonding profiles. The hydrogen bond (H-bond) stability is explained by tracking donor-acceptor distances and angles over time, using calculations such as possession and firmness represented through their persistence against thermal instabilities, expressing their role in structure and function, frequently heightened for prediction beyond simple energy [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Consequently, the screened potent small phytocompounds followed the five rules of Lipinski as represented by the drug likeness characteristics through filter competency [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Subsequently, the β-sitosterol was performed considerable interactions with three selected targets whereas the significant interaction was made with DPP-4.\u003c/p\u003e \u003cp\u003eTherefore, further experimentations were performed for the \u003cem\u003ein-vivo\u003c/em\u003e assessments. The \u003cem\u003ein-vivo\u003c/em\u003e studies revealed that the cytotoxic mode of action of streptozotocin in nicotinamide treated animal resulted in hyperglycemia through dysfunctions of β-cells, reduced sensitivity, and insulin resistance[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. The treatment of test extract caused significant improvements in HOMA indices (insulin resistance, β-cell sensitivity, and function) as revealed through pancreatic histology. Supportively, the oxidative stress was reduced through the treatments of test extract and sitagliptin, which indicates the synchronizing mode of action of the potent phytocompounds. It is depicted through numerous studies that reduced oxidative stress promotes restorations by subsiding the degenerative changes through scavenging the free radicals and support to regularizing of the key metabolic pathways[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. The glucose and lipid metabolisms are linked with each other\u0026rsquo;s which are altered significantly through the treatments of the test extract. It can be represented through interactions of small molecules phytocompound with key metabolic enzymes (α-amylase, α-glycosidase, and DPP-4), and their inhibition resulted in reduced glucose levels as well as improved lipid profile, as reported by earlier studies [\u003cspan additionalcitationids=\"CR46\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. The collective interpretations of the improved histoarchitectures of the pancreases, reduced glucose levels, ameliorated lipid profile, and improved oxidative stress can be expressed through interactions of selected phytocompounds, which have significant capabilities to ameliorate the hyperglycemia by following the synchronized action through multitargeted pathways.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe study represents the existence of the twelve potent phytocompounds of the methanolic fruit extract of \u003cem\u003eCordia myxa\u003c/em\u003e L. (MECMF), which have the capabilities to interact with selected targets particularly β-sitosterol, Cordiaquinone C, and Cordiaquinone G that displayed strong inhibitory potential against DPP-4, α-amylase, and α-glycosidase, respectively. Subsequently, \u003cem\u003ein-vivo\u003c/em\u003e evaluations validate the multitargeted interactions of the selected coonhounds through biochemical as well as histological assessments. These integrated findings substantiate the traditional use of \u003cem\u003eC. myxa\u003c/em\u003e and establish MECMF as a promising multitarget natural therapeutic candidate for managing type 2 diabetes mellitus. Further isolation and characterization of its active compounds may accelerate the development of safe, plant-derived antidiabetic agents.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors sincerely acknowledged the kind cooperation of the department of Zoology, Jai Narain Vyas University, Jodhpur (Rajasthan) for the providing required facilities and ethical approval.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor’s contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChandra Kala \u0026amp; Kavita Kumari Gaur\u003csup\u003e\u0026nbsp;\u003c/sup\u003e– Investigation and experimentations; Kamlesh Kumar, Rajat Raja and Kirti Rathore\u003csup\u003e\u0026nbsp;\u003c/sup\u003e– Data compilation and original drafting; Surbhi Ranga \u0026amp; Mukesh Kumar\u003csup\u003e\u0026nbsp;\u003c/sup\u003e– Review \u0026amp; Editing and Heera Ram\u003csup\u003e\u0026nbsp;\u003c/sup\u003e– Conceptualization \u0026amp; Supervision.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData can be provided on the request with permission of the research team for positive rational.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe plant \u003cem\u003eCordia myxa\u0026nbsp;\u003c/em\u003eL. was identified and authenticated by the Botanical Survey of India (BSI), Jodhpur, Rajasthan (\u003cstrong\u003eBSI/AZRC/I.12012/Tech./2021-22 (PI.Id.)/ 146)\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnimal protocols were approved by the Institutional Ethical Committee (IAEC) (Registration no.\u003cstrong\u003e\u0026nbsp;1646/GO/Ere/S/12/CCSEA)\u003c/strong\u003e, and the animals were followed according to the guidelines from CCSEA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any specific grant from funding agencies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflict of interest\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRanjbar, M., Varzi, H. 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Effects of 22 traditional anti-diabetic medicinal plants on DPP-IV enzyme activity and glucose homeostasis in high-fat fed obese diabetic rats. \u003cem\u003eBioscience Reports\u003c/em\u003e, \u003cem\u003e41\u003c/em\u003e(1), BSR20203824. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1042/BSR20203824\u003c/span\u003e\u003cspan address=\"10.1042/BSR20203824\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"applied-biochemistry-and-biotechnology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"abab","sideBox":"Learn more about [Applied Biochemistry and Biotechnology](https://www.springer.com/journal/12010)","snPcode":"12010","submissionUrl":"https://submission.nature.com/new-submission/12010/3","title":"Applied Biochemistry and Biotechnology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cordia myxa L., medicinal plant, antidiabetic, phytochemicals, DPP-4, antioxidant","lastPublishedDoi":"10.21203/rs.3.rs-8824801/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8824801/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe current study aimed to investigate the multitargeted antidiabetic potential of the methanolic extract of \u003cem\u003eC. myxa\u003c/em\u003e fruits (MECMF) through \u003cem\u003ein-silico\u003c/em\u003e and \u003cem\u003ein-vivo\u003c/em\u003e assessments. Chemical fingerprinting of the test extract was performed using LC\u0026ndash;MS/MS, with authentication of the UNIFI scientific library database. Potent phytocompounds were screened out by using the protein ligand molecular docking against the multitargets (dipeptidyl peptidase-4 (DPP-4), α-amylase, and α-glycosidase) through assessments of binding energy and related parameters. Further validation of interactions with target proteins was examined by following the molecular dynamics simulations at 1ns with the standard conditions by calculations of RSMD, and hydrogen bond profiling. The assessments of molecular dynamic simulation showed significant interactions by the selected three complexes \u003cem\u003ei.e\u003c/em\u003e., DPP-4 -β-sitosterol, α-amylase-cordiaquinone C, and α-glycosidase-cordiaquinone G. ADMET revealed substantial drug likeness characteristics of the screened phytocompounds. Consequently, the nicotinamide\u0026ndash;streptozotocin\u0026ndash;induced type 2 diabetic rat model was utilized for biochemical and histological studies. The treatment of the test extract and standard drug (sitagliptin) showed alterations in HOMA indices, lipid metabolism, oxidative stress, and histology of the pancreas. Substantial improvements were revealed by the treatment of the test extract in the histoarchitectures of pancreases through reducing the degenerative changes. These kinds of alterations were followed by the ameliorated oxidative stress through significant improvements in the FRAP, GSH, and LPO. Collectively, it can be concluded that phytocompounds of the \u003cem\u003eC. myxa\u003c/em\u003e have capabilities to interfere in glucose metabolism through a multitargeted approach. Further experimentation can be promoting the drug development practices for the therapeutics of diabetes.\u003c/p\u003e","manuscriptTitle":"Multitargeted antidiabetic intervention of phytocompounds of methanolic fruit extract of Cordia myxa L.: Integrated from in-silico and in-vivo studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-04 05:25:10","doi":"10.21203/rs.3.rs-8824801/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Resubmit revised form; Major revisions required","date":"2026-03-22T03:08:23+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-02-26T02:10:48+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-26T01:47:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Applied Biochemistry and Biotechnology","date":"2026-02-25T03:44:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-20T03:34:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Applied Biochemistry and Biotechnology","date":"2026-02-17T11:42:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"applied-biochemistry-and-biotechnology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"abab","sideBox":"Learn more about [Applied Biochemistry and Biotechnology](https://www.springer.com/journal/12010)","snPcode":"12010","submissionUrl":"https://submission.nature.com/new-submission/12010/3","title":"Applied Biochemistry and Biotechnology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5fbb8fe1-a6fe-4893-9b6e-05cfe09ecf28","owner":[],"postedDate":"March 4th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-08T02:18:51+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-04 05:25:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8824801","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8824801","identity":"rs-8824801","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}