Stacked ensemble learning and in-silico profiling reveal dual DPP-IV and SGLT2 Inhibitors from Moringa oleifera metabolites

Stacked ensemble learning and in-silico profiling reveal dual DPP-IV and SGLT2 Inhibitors from Moringa oleifera metabolites | 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 Stacked ensemble learning and in-silico profiling reveal dual DPP-IV and SGLT2 Inhibitors from Moringa oleifera metabolites Letuku MK, Mohlala MG, Nuapia YB This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7954666/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted 17 You are reading this latest preprint version Abstract Diabetes mellitus (DM) is a growing global health challenge, particularly in low-resource settings where access to effective therapies remains limited. Dual inhibition of dipeptidyl peptidase IV (DPP-IV) and sodium–glucose co-transporter 2 (SGLT2) offers a synergistic therapeutic strategy by enhancing insulin secretion and promoting glucose excretion. This study developed an integrated in silico framework combining stacked ensemble machine learning, molecular docking, and ADMET profiling to identify dual DPP-IV/SGLT2 inhibitors from M. oleifera metabolites. Baseline models were generated using 110 algorithm–descriptor combinations per target, and stacking significantly improved predictive accuracy, achieving strong performance with Matthews Correlation Coefficients of 0.968 (training) and 0.937 (testing) for DPP-IV, and 0.968 (training) and 0.861 (testing) for SGLT2. Validation against FDA-approved inhibitors confirmed the models’ reliability and generalisability. LC–MS/MS profiling of M. oleifera revealed several metabolites with high predicted activity, among which vitexin, homoorientin, lariciresinol 4-O-β-D-glucopyranoside, and N,α-L-rhamnopyranosyl vincosamide showed strong binding affinities and favourable pharmacokinetic properties. The findings highlight M. oleifera as a promising source of multitarget antidiabetic compounds and demonstrate the potential of stacked ensemble learning in accelerating natural product-based drug discovery. Biological sciences/Computational biology and bioinformatics Biological sciences/Drug discovery M. oleifera stacked ensemble learning DPP IV SGLT2 natural product drug discovery Full Text Additional Declarations Competing interest reported. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Supplementary Files Highlights.docx Supplementaryinformationfile.docx Graphicalabstract002.tif Cite Share Download PDF Status: Published Journal Publication published 18 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 24 Nov, 2025 Reviews received at journal 24 Nov, 2025 Reviews received at journal 22 Nov, 2025 Reviews received at journal 22 Nov, 2025 Reviews received at journal 21 Nov, 2025 Reviewers agreed at journal 16 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviews received at journal 15 Nov, 2025 Reviewers agreed at journal 06 Nov, 2025 Reviewers invited by journal 29 Oct, 2025 Editor invited by journal 29 Oct, 2025 Editor assigned by journal 27 Oct, 2025 Submission checks completed at journal 27 Oct, 2025 First submitted to journal 26 Oct, 2025 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. 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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-7954666","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":541950626,"identity":"0e4b63fc-c0e9-40a2-9d10-0b38376fa1a0","order_by":0,"name":"Letuku MK","email":"","orcid":"","institution":"University of Limpopo","correspondingAuthor":false,"prefix":"","firstName":"Letuku","middleName":"","lastName":"MK","suffix":""},{"id":541950627,"identity":"d0f9c4e3-ae3f-4010-a83c-155001eda27a","order_by":1,"name":"Mohlala MG","email":"","orcid":"","institution":"University of 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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","formattedTitle":"Stacked ensemble learning and in-silico profiling reveal dual DPP-IV and SGLT2 Inhibitors from Moringa oleifera metabolites","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"M. oleifera, stacked ensemble learning, DPP IV, SGLT2, natural product drug discovery","lastPublishedDoi":"10.21203/rs.3.rs-7954666/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7954666/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDiabetes mellitus (DM) is a growing global health challenge, particularly in low-resource settings where access to effective therapies remains limited. Dual inhibition of dipeptidyl peptidase IV (DPP-IV) and sodium–glucose co-transporter 2 (SGLT2) offers a synergistic therapeutic strategy by enhancing insulin secretion and promoting glucose excretion. This study developed an integrated in silico framework combining stacked ensemble machine learning, molecular docking, and ADMET profiling to identify dual DPP-IV/SGLT2 inhibitors from \u003cem\u003eM. oleifera\u003c/em\u003emetabolites. Baseline models were generated using 110 algorithm–descriptor combinations per target, and stacking significantly improved predictive accuracy, achieving strong performance with Matthews Correlation Coefficients of 0.968 (training) and 0.937 (testing) for DPP-IV, and 0.968 (training) and 0.861 (testing) for SGLT2. Validation against FDA-approved inhibitors confirmed the models’ reliability and generalisability. LC–MS/MS profiling of \u003cem\u003eM. oleifera\u003c/em\u003e revealed several metabolites with high predicted activity, among which vitexin, homoorientin, lariciresinol 4-O-β-D-glucopyranoside, and N,α-L-rhamnopyranosyl vincosamide showed strong binding affinities and favourable pharmacokinetic properties. The findings highlight \u003cem\u003eM. oleifera\u003c/em\u003eas a promising source of multitarget antidiabetic compounds and demonstrate the potential of stacked ensemble learning in accelerating natural product-based drug discovery.\u003c/p\u003e","manuscriptTitle":"Stacked ensemble learning and in-silico profiling reveal dual DPP-IV and SGLT2 Inhibitors from Moringa oleifera metabolites","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 10:17:52","doi":"10.21203/rs.3.rs-7954666/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-24T05:51:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-24T05:18:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-22T10:09:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-22T08:04:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-21T07:36:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"122767937288042741726342172281986254783","date":"2025-11-16T14:03:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"304361532712639641137950922826206495565","date":"2025-11-16T04:42:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30497865630184455339873509913444001275","date":"2025-11-16T03:20:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"329581494102287422735500104908632421004","date":"2025-11-16T02:42:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333167298873040748125825642381371365872","date":"2025-11-15T23:04:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-15T10:36:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"151145938305636006608178296781805307583","date":"2025-11-06T06:19:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-29T13:35:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-29T13:14:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-27T07:48:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-27T07:45:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-10-26T16:46:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bcb36fd8-9dad-4add-b46a-6e13d46d4e79","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":57658677,"name":"Biological sciences/Computational biology and bioinformatics"},{"id":57658678,"name":"Biological sciences/Drug discovery"}],"tags":[],"updatedAt":"2026-02-23T16:07:24+00:00","versionOfRecord":{"articleIdentity":"rs-7954666","link":"https://doi.org/10.1038/s41598-026-39960-z","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-02-18 15:59:03","publishedOnDateReadable":"February 18th, 2026"},"versionCreatedAt":"2025-11-10 10:17:52","video":"","vorDoi":"10.1038/s41598-026-39960-z","vorDoiUrl":"https://doi.org/10.1038/s41598-026-39960-z","workflowStages":[]},"version":"v1","identity":"rs-7954666","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7954666","identity":"rs-7954666","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}