Structure-Based Virtual Screening and Discovery of Novel Thiazole Derivatives as Potential PPARγ Modulators for Type 2 Diabetes Mellitus

Structure-Based Virtual Screening and Discovery of Novel Thiazole Derivatives as Potential PPARγ Modulators for Type 2 Diabetes Mellitus | 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 Structure-Based Virtual Screening and Discovery of Novel Thiazole Derivatives as Potential PPARγ Modulators for Type 2 Diabetes Mellitus Saminesh Kumar, Shivank Sharma, Stalin Arulsamy, Vanktesh Kumar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8894257/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 Introduction: Type 2 diabetes mellitus (T2DM) is a major metabolic disorder marked by insulin resistance and impaired β-cell function. Peroxisome proliferator-activated receptor gamma (PPARγ) serves as a key nuclear receptor regulating glucose and lipid metabolism. While thiazolidinedione (TZD) drugs effectively activate PPARγ, their clinical use is restricted due to adverse effects, highlighting the need for safer, selective modulators . Materials and Methods: An integrated in silico workflow was applied using the crystal structure of human PPARγ (PDB ID: 6ONJ). A virtual library of thiazole derivatives (SS-01 to SS-50) was screened through Lipinski’s rule, ADMET profiling, molecular docking, and density functional theory (DFT) analyses to predict binding affinity, pharmacokinetics, and toxicity. Results: Most compounds satisfied Lipinski’s criteria, exhibiting high predicted intestinal absorption (>85%) and balanced distribution properties. Docking studies identified several potent hits (SS-11 to SS-16) with strong binding affinities (−9.4 to −11.2 kcal/mol) and key hydrogen-bond interactions with Tyr473, His323, and Ser289. ADMET data indicated good oral bioavailability, moderate clearance, and low predicted toxicity, with minimal CYP inhibition and non-hepatotoxic profiles for top candidates. Discussion: The study revealed that selected thiazole derivatives display comparable or superior PPARγ binding relative to rosiglitazone, with improved safety profiles. Quantum chemical parameters supported their electronic suitability and receptor stability. Conclusion: This structure-based virtual screening identified novel thiazole-based scaffolds as promising PPARγ modulators with favorable pharmacokinetic and safety attributes, providing a strong foundation for synthesis and experimental validation as next-generation antidiabetic agents. Thiazole derivatives Molecular docking DFT analysia Full Text Additional Declarations No competing interests reported. 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-8894257","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":600900837,"identity":"7252df0b-0333-44db-85d6-775dcefc83db","order_by":0,"name":"Saminesh Kumar","email":"","orcid":"","institution":"Lovely Professional University","correspondingAuthor":false,"prefix":"","firstName":"Saminesh","middleName":"","lastName":"Kumar","suffix":""},{"id":600900841,"identity":"841e4479-3e1b-4445-bf27-c5babd9f8b87","order_by":1,"name":"Shivank Sharma","email":"","orcid":"","institution":"Lovely Professional University","correspondingAuthor":false,"prefix":"","firstName":"Shivank","middleName":"","lastName":"Sharma","suffix":""},{"id":600900844,"identity":"0f389dbd-deff-4442-aa56-19fa8f4f7edb","order_by":2,"name":"Stalin Arulsamy","email":"","orcid":"","institution":"Lovely Professional University","correspondingAuthor":false,"prefix":"","firstName":"Stalin","middleName":"","lastName":"Arulsamy","suffix":""},{"id":600900845,"identity":"c0957eba-4d84-4f49-afde-36c0f2aed058","order_by":3,"name":"Vanktesh Kumar","email":"data:image/png;base64,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","orcid":"","institution":"Lovely Professional University","correspondingAuthor":true,"prefix":"","firstName":"Vanktesh","middleName":"","lastName":"Kumar","suffix":""}],"badges":[],"createdAt":"2026-02-16 15:09:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8894257/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8894257/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107437250,"identity":"cd983196-89aa-4801-8a75-2a822fe289e6","added_by":"auto","created_at":"2026-04-21 13:27:57","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1759534,"visible":true,"origin":"","legend":"","description":"","filename":"ManiscriptPPARGAMMAnew.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8894257/v1_covered_a9b004de-382e-427b-8cd9-e0e0ecca98af.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Structure-Based Virtual Screening and Discovery of Novel Thiazole Derivatives as Potential PPARγ Modulators for Type 2 Diabetes Mellitus","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":"Thiazole derivatives, Molecular docking, DFT analysia","lastPublishedDoi":"10.21203/rs.3.rs-8894257/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8894257/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003cbr\u003e\n \u003c/strong\u003eType 2 diabetes mellitus (T2DM) is a major metabolic disorder marked by insulin resistance and impaired β-cell function. Peroxisome proliferator-activated receptor gamma (PPARγ) serves as a key nuclear receptor regulating glucose and lipid metabolism. While thiazolidinedione (TZD) drugs effectively activate PPARγ, their clinical use is restricted due to adverse effects, highlighting the need for safer, selective modulators\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and Methods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn integrated in silico workflow was applied using the crystal structure of human PPARγ (PDB ID: 6ONJ). A virtual library of thiazole derivatives (SS-01 to SS-50) was screened through Lipinski’s rule, ADMET profiling, molecular docking, and density functional theory (DFT) analyses to predict binding affinity, pharmacokinetics, and toxicity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003cbr\u003e\n \u003c/strong\u003eMost compounds satisfied Lipinski’s criteria, exhibiting high predicted intestinal absorption (\u0026gt;85%) and balanced distribution properties. Docking studies identified several potent hits (SS-11 to SS-16) with strong binding affinities (−9.4 to −11.2 kcal/mol) and key hydrogen-bond interactions with Tyr473, His323, and Ser289. ADMET data indicated good oral bioavailability, moderate clearance, and low predicted toxicity, with minimal CYP inhibition and non-hepatotoxic profiles for top candidates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion:\u003cbr\u003e\n \u003c/strong\u003eThe study revealed that selected thiazole derivatives display comparable or superior PPARγ binding relative to rosiglitazone, with improved safety profiles. Quantum chemical parameters supported their electronic suitability and receptor stability.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003cbr\u003e\n \u003c/strong\u003eThis structure-based virtual screening identified novel thiazole-based scaffolds as promising PPARγ modulators with favorable pharmacokinetic and safety attributes, providing a strong foundation for synthesis and experimental validation as next-generation antidiabetic agents.\u003c/p\u003e","manuscriptTitle":"Structure-Based Virtual Screening and Discovery of Novel Thiazole Derivatives as Potential PPARγ Modulators for Type 2 Diabetes Mellitus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-06 09:28:24","doi":"10.21203/rs.3.rs-8894257/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":"8ddce1af-07ff-49b7-a4e0-bbe5a2309b21","owner":[],"postedDate":"March 6th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-21T13:26:07+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-06 09:28:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8894257","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8894257","identity":"rs-8894257","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}