Probing the Binding Ability of Quinoxaline Derivatives towards Tau Protein: A Theoretical Insight

Probing the Binding Ability of Quinoxaline Derivatives towards Tau Protein: A Theoretical Insight | 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 Probing the Binding Ability of Quinoxaline Derivatives towards Tau Protein: A Theoretical Insight Sagar Bagwe, Ayesha Khan, Venkatanarayana Pappula, Gurunath Suryavanshi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7582243/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The aggregation of tau proteins is a characteristic feature of several neurodegenerative disorders, including Alzheimer's disease. In this study, a computational approach was employed to identify and evaluate potential small-molecule ligands targeting the Tau protein. Ten ligands were initially screened using molecular docking with AutoDock 4.2, revealing Ligand 10 as the most promising candidate, exhibiting the strongest binding energy (–7.39 kcal/mol), multiple hydrogen bonds, and interactions with eight Tau residues. Key amino acids such as Asn359, Gly367, and Phe346 emerged as frequent binding sites, indicating potential hotspots within the Tau binding region (residues 320–370). Additionally, Molecular Electrostatic Potential (MESP) analysis on optimized ligand structures identified the most reactive regions, primarily around carbonyl and nitrogen-containing functional groups. To gain deeper insights into the electronic nature of ligand–Tau interactions, DFT calculations were performed using the wB97XD/6-311 + G(d,p) method on model Tau–ligand complexes. The results supported the docking findings, with Ligand 10 showing the most favorable interaction energy (–49.9 kcal/mol). Together, these results highlight Ligands 10, 2, and 9 as promising leads for further experimental validation and optimization. This integrated computational framework provides valuable direction for the rational design of Tau-targeted therapeutics for neurodegenerative disorders. The in silico prediction of ADME properties also indicated that the proposed ligand molecules possess notable drug-likeness characteristics. Quinoxaline Docking DFT Studies Tau Protein Binding Energy Full Text Additional Declarations No competing interests reported. Supplementary Files SupportingInformation.doc Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7582243","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":537340592,"identity":"aaa3cf39-5464-4479-868b-ff9c6cbdf419","order_by":0,"name":"Sagar Bagwe","email":"","orcid":"","institution":"Savitribai Phule Pune University","correspondingAuthor":false,"prefix":"","firstName":"Sagar","middleName":"","lastName":"Bagwe","suffix":""},{"id":537340595,"identity":"6cff3a61-ed71-4326-a343-652d5f8fd24f","order_by":1,"name":"Ayesha Khan","email":"","orcid":"","institution":"Savitribai Phule Pune 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Insight","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Quinoxaline, Docking, DFT Studies, Tau Protein, Binding Energy","lastPublishedDoi":"10.21203/rs.3.rs-7582243/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7582243/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe aggregation of tau proteins is a characteristic feature of several neurodegenerative disorders, including Alzheimer's disease. In this study, a computational approach was employed to identify and evaluate potential small-molecule ligands targeting the Tau protein. Ten ligands were initially screened using molecular docking with AutoDock 4.2, revealing Ligand 10 as the most promising candidate, exhibiting the strongest binding energy (\u0026ndash;7.39 kcal/mol), multiple hydrogen bonds, and interactions with eight Tau residues. Key amino acids such as Asn359, Gly367, and Phe346 emerged as frequent binding sites, indicating potential hotspots within the Tau binding region (residues 320\u0026ndash;370). Additionally, Molecular Electrostatic Potential (MESP) analysis on optimized ligand structures identified the most reactive regions, primarily around carbonyl and nitrogen-containing functional groups. To gain deeper insights into the electronic nature of ligand\u0026ndash;Tau interactions, DFT calculations were performed using the wB97XD/6-311\u0026thinsp;+\u0026thinsp;G(d,p) method on model Tau\u0026ndash;ligand complexes. The results supported the docking findings, with Ligand 10 showing the most favorable interaction energy (\u0026ndash;49.9 kcal/mol). Together, these results highlight Ligands 10, 2, and 9 as promising leads for further experimental validation and optimization. This integrated computational framework provides valuable direction for the rational design of Tau-targeted therapeutics for neurodegenerative disorders. The \u003cem\u003ein silico\u003c/em\u003e prediction of ADME properties also indicated that the proposed ligand molecules possess notable drug-likeness characteristics.\u003c/p\u003e","manuscriptTitle":"Probing the Binding Ability of Quinoxaline Derivatives towards Tau Protein: A Theoretical Insight","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-07 18:48:41","doi":"10.21203/rs.3.rs-7582243/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4efa893f-409d-4c67-bebc-9dc29f2de0a1","owner":[],"postedDate":"November 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-23T22:38:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-07 18:48:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7582243","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7582243","identity":"rs-7582243","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}