Unveiling Druggable Segments in Klebsiella pneumoniae KPHS_11890: An Integrated DRKG- MD Study

Unveiling Druggable Segments in Klebsiella pneumoniae KPHS_11890: An Integrated DRKG- MD Study | 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 Unveiling Druggable Segments in Klebsiella pneumoniae KPHS_11890: An Integrated DRKG- MD Study Zhenghua Jiang, Mengqi Huang, Yemei Bu, Siqi Wu, Sijun Meng, Zhaochun Wu, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7812671/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Dec, 2025 Read the published version in Journal of Computer-Aided Molecular Design → Version 1 posted 10 You are reading this latest preprint version Abstract Klebsiella pneumoniae (K. pneumoniae) , a multidrug-resistant Gram-negative bacillus, represents a significant global health threat due to its role in hospital-acquired infections and the emergence of carbapenem-resistant hypervirulent strains. This study integrates the Drug Repurposing Knowledge Graph (DRKG) with molecular dynamics (MD) simulations to identify and validate stable structural segments of the KPHS_11890 gene, which encodes a membrane fusion protein of the AcrAB-TolC efflux pump that is critical for antibiotic resistance in K. pneumoniae . Using the PyKEEN framework, a knowledge graph embedding model was trained on a comprehensive dataset combining DrugBank, K. pneumoniae strain FASTA sequences, and NCBI databases, achieving a Hits@10 score of 0.1602 and an adjusted arithmetic mean rank of 0.0238. The model predicted KPHS_11890 as a top candidate, validated by 100-ns molecular dynamics simulations using Amber 24, which revealed stable segments in the α-helical domain, the extended strand domain, and the random coil domain. These segments, identified through low root mean square fluctuation (RMSF) values and conserved secondary structures, are critical for AcrA interactions with AcrB and TolC, offering potential drug-binding sites for efflux pump inhibitors. This integrated DRKG-MD approach efficiently pinpoints high-potential targets and elucidates their structural basis, thereby accelerating the development of novel anti-resistance therapeutics. Klebsiella pneumoniae knowledge graph molecular dynamics simulation antibiotic resistance drug target identification Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.zip Cite Share Download PDF Status: Published Journal Publication published 29 Dec, 2025 Read the published version in Journal of Computer-Aided Molecular Design → Version 1 posted Editorial decision: Revision requested 10 Nov, 2025 Reviews received at journal 24 Oct, 2025 Reviewers agreed at journal 23 Oct, 2025 Reviews received at journal 21 Oct, 2025 Reviewers agreed at journal 21 Oct, 2025 Reviewers agreed at journal 14 Oct, 2025 Reviewers invited by journal 14 Oct, 2025 Editor assigned by journal 13 Oct, 2025 Submission checks completed at journal 09 Oct, 2025 First submitted to journal 08 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-7812671","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":534633622,"identity":"e7ae0e3e-21c8-4d35-876d-3cd8d90c97da","order_by":0,"name":"Zhenghua 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Study","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":"journal-of-computer-aided-molecular-design","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcam","sideBox":"Learn more about [Journal of Computer-Aided Molecular Design](http://link.springer.com/journal/10822)","snPcode":"10822","submissionUrl":"https://submission.nature.com/new-submission/10822/3","title":"Journal of Computer-Aided Molecular Design","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Klebsiella pneumoniae, knowledge graph, molecular dynamics simulation, antibiotic resistance, drug target identification","lastPublishedDoi":"10.21203/rs.3.rs-7812671/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7812671/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eKlebsiella pneumoniae (K. pneumoniae)\u003c/em\u003e, a multidrug-resistant Gram-negative bacillus, represents a significant global health threat due to its role in hospital-acquired infections and the emergence of carbapenem-resistant hypervirulent strains. This study integrates the Drug Repurposing Knowledge Graph (DRKG) with molecular dynamics (MD) simulations to identify and validate stable structural segments of the KPHS_11890 gene, which encodes a membrane fusion protein of the AcrAB-TolC efflux pump that is critical for antibiotic resistance in \u003cem\u003eK. pneumoniae\u003c/em\u003e. Using the PyKEEN framework, a knowledge graph embedding model was trained on a comprehensive dataset combining DrugBank, \u003cem\u003eK. pneumoniae\u003c/em\u003e strain FASTA sequences, and NCBI databases, achieving a Hits@10 score of 0.1602 and an adjusted arithmetic mean rank of 0.0238. The model predicted KPHS_11890 as a top candidate, validated by 100-ns molecular dynamics simulations using Amber 24, which revealed stable segments in the α-helical domain, the extended strand domain, and the random coil domain. These segments, identified through low root mean square fluctuation (RMSF) values and conserved secondary structures, are critical for AcrA interactions with AcrB and TolC, offering potential drug-binding sites for efflux pump inhibitors. This integrated DRKG-MD approach efficiently pinpoints high-potential targets and elucidates their structural basis, thereby accelerating the development of novel anti-resistance therapeutics.\u003c/p\u003e","manuscriptTitle":"Unveiling Druggable Segments in Klebsiella pneumoniae KPHS_11890: An Integrated DRKG- MD Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-29 05:17:58","doi":"10.21203/rs.3.rs-7812671/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-10T21:30:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-24T06:12:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"43809823511575996952529451206374264309","date":"2025-10-23T13:22:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-21T11:01:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"209658616104473081746560740085737974306","date":"2025-10-21T05:25:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"290396998861037363881669267939847191403","date":"2025-10-15T03:33:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-14T19:04:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-14T01:48:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-10T03:50:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Computer-Aided Molecular Design","date":"2025-10-09T03:39:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-computer-aided-molecular-design","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcam","sideBox":"Learn more about [Journal of Computer-Aided Molecular Design](http://link.springer.com/journal/10822)","snPcode":"10822","submissionUrl":"https://submission.nature.com/new-submission/10822/3","title":"Journal of Computer-Aided Molecular Design","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0e701c7e-17c5-46ea-8496-67451087606e","owner":[],"postedDate":"October 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T16:01:04+00:00","versionOfRecord":{"articleIdentity":"rs-7812671","link":"https://doi.org/10.1007/s10822-025-00741-x","journal":{"identity":"journal-of-computer-aided-molecular-design","isVorOnly":false,"title":"Journal of Computer-Aided Molecular Design"},"publishedOn":"2025-12-29 15:57:59","publishedOnDateReadable":"December 29th, 2025"},"versionCreatedAt":"2025-10-29 05:17:58","video":"","vorDoi":"10.1007/s10822-025-00741-x","vorDoiUrl":"https://doi.org/10.1007/s10822-025-00741-x","workflowStages":[]},"version":"v1","identity":"rs-7812671","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7812671","identity":"rs-7812671","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}