Network Pharmacology-guided Identification and Molecular Validation of Multi-Target Phytoconstituents from Gmelina arborea against Alzheimer’s Disease

Network Pharmacology-guided Identification and Molecular Validation of Multi-Target Phytoconstituents from Gmelina arborea against Alzheimer’s Disease | 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 Article Network Pharmacology-guided Identification and Molecular Validation of Multi-Target Phytoconstituents from Gmelina arborea against Alzheimer’s Disease Amit Gangwal, Azim Ansari, Iqrar Ansari, Jyotiram A. Sawale This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7399280/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Alzheimer’s disease (AD), one of the most prevalent neurodegenerative disorders, remains without a definitive cure due to its complex multifactorial pathogenesis. Conventional drug development strategies, targeting single pathway, have demonstrated limited success, necessitating a paradigm shift towards multi-target therapeutics. In this study, we systematically investigated the therapeutic potential of Gmelina arborea (GA), a medicinal plant used in traditional Indian medicine against dementia, using an integrated network pharmacology and molecular modeling approach. Phytoconstituents of GA (GAPC) were selected and screened for drug-likeness (DL), blood-brain barrier (BBB) permeability, and absorption, distribution, metabolism, excretion, and toxicology (ADMET) properties. Potential therapeutic targets of GAPC were predicted and cross-referenced with known AD-associated targets to construct a protein-protein interaction (PPI) network of common targets. Functional enrichment analysis revealed key aspects of gene ontology (GO) and pathways, including PI3K-Akt, MAPK, FoxO, Rap1, and Ras signaling pathways. Top ten core target genes (using topological analysis) were identified as AKT1, EGFR, ESR1, SRC, PTGS2, GSK3β, MMP9, PARP1, KDR, and ABCB1. Molecular docking, molecular dynamics (MD) simulations, molecular mechanics, the Generalized Born Surface Area (MM-GBSA), principal component analysis (PCA), and free energy landscape (FEL) analysis confirmed strong, stable binding interactions, especially for verbascoside and martynoside. This study provides compelling evidence that GA can be targeted for AD treatment following experimental validation and lays the foundation for further wet lab investigations. It also presents the first integrated in silico and network pharmacology analysis of GAPC's multi-target interactions in AD, offering mechanistic insights to guide future research. Biological sciences/Computational biology and bioinformatics Biological sciences/Drug discovery Biological sciences/Neuroscience Acetylcholinesterase Alzheimer’s Disease BACE1 Free Energy Landscape Gmelina arborea Martynoside MM-GBSA Molecular Docking Molecular Dynamics Simulation Multi-Target Therapy Network Pharmacology Neuroprotection Principal Component Analysis Phytoconstituents Tau protein Verbascoside Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryFile.xls Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7399280","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":505692055,"identity":"289189f2-83a8-4e90-b2c1-02b04d33da83","order_by":0,"name":"Amit Gangwal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYPACCyBmbGD4AKTY2InTIgHS0tg4A6SFmXgtDIzNPCCKkBZ597OHX/PUSDDwTzvc/tjm1zZ5PmYGxg8fc3BrMTyTl2bNc0yCQeJ2YmNzbt9twzZmBmbJmdvwaGnIMTPOYQM6DKyl5zYjUAsbMy8+Lf1vgFr+STDIg7RY9ty2J6hFXiLH+HFumwSDAUgLw4/biQS1GEi8MWP+2yfBYwjUMrO34XZyGzNjM16/yPfnGH+c8c1GTu52+oMPP/7ctp3f3nzww0d8thxgAPmdARwjDIxtYLIBt3qQLQ0MzB8Q3D94FY+CUTAKRsEIBQBRZE/7UyaYlAAAAABJRU5ErkJggg==","orcid":"","institution":"SVKM NMIMS Global University","correspondingAuthor":true,"prefix":"","firstName":"Amit","middleName":"","lastName":"Gangwal","suffix":""},{"id":505692056,"identity":"0c6baede-de6d-4165-80ce-25de3895ec8b","order_by":1,"name":"Azim Ansari","email":"","orcid":"","institution":"SVKM NMIMS Global University","correspondingAuthor":false,"prefix":"","firstName":"Azim","middleName":"","lastName":"Ansari","suffix":""},{"id":505692057,"identity":"2b6fc119-e3be-44f4-be9a-037823fc1f87","order_by":2,"name":"Iqrar Ansari","email":"","orcid":"","institution":"Prof. Ravindra Nikam College of Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Iqrar","middleName":"","lastName":"Ansari","suffix":""},{"id":505692058,"identity":"eabd964c-7229-4629-973b-2d184dbb6f64","order_by":3,"name":"Jyotiram A. 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Conventional drug development strategies, targeting single pathway, have demonstrated limited success, necessitating a paradigm shift towards multi-target therapeutics. In this study, we systematically investigated the therapeutic potential of \u003cem\u003eGmelina arborea\u003c/em\u003e (GA), a medicinal plant used in traditional Indian medicine against dementia, using an integrated network pharmacology and molecular modeling approach. Phytoconstituents of GA (GAPC) were selected and screened for drug-likeness (DL), blood-brain barrier (BBB) permeability, and absorption, distribution, metabolism, excretion, and toxicology (ADMET) properties. Potential therapeutic targets of GAPC were predicted and cross-referenced with known AD-associated targets to construct a protein-protein interaction (PPI) network of common targets. Functional enrichment analysis revealed key aspects of gene ontology (GO) and pathways, including PI3K-Akt, MAPK, FoxO, Rap1, and Ras signaling pathways. 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