Pose-Rescorer: A Deterministic Single-Frame MM/GBSA Workflow for Post-Docking Ligand Ranking

Pose-Rescorer: A Deterministic Single-Frame MM/GBSA Workflow for Post-Docking Ligand Ranking | 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 Pose-Rescorer: A Deterministic Single-Frame MM/GBSA Workflow for Post-Docking Ligand Ranking Amirtesh Raghuram This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9125641/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 Molecular docking is widely used for large-scale virtual screening, yet its empirical scoring functions are approximate and often fail to capture the balance between intermolecular interactions and solvation. Molecular dynamics–based free-energy methods can address these limitations but are computationally expensive, non-deterministic, and impractical for routine post-docking prioritization. Here, we present Pose-Rescorer, a chemistry-first, deterministic post-docking rescoring tool that applies single-frame MM/GBSA or MM/PBSA calculations to minimized protein–ligand complexes for relative pose and ligand ranking. Pose-Rescorer enforces strict chemical correctness by requiring explicit ligand connectivity, GAFF2 parameterization with AM1-BCC charges, and a fixed receptor context, ensuring internal comparability of scores. The workflow performs restrained generalized Born minimization followed by single-structure MM/GBSA or MM/PBSA evaluation without molecular dynamics, conformational sampling, or entropy estimation; consequently, scores are not interpreted as physical binding free energies but are intended solely for relative ranking within a consistent receptor system. To complement single-frame rescoring, Pose-Rescorer optionally incorporates Rapid Perturbation Sampling (RPS), a reproducible diagnostic procedure that quantifies the numerical sensitivity of MM/GBSA scores to small coordinate perturbations. Worked examples using kinase, protease, bromodomain, and chaperone systems demonstrate how Pose-Rescorer refines docking-derived ligand prioritization. Pose-Rescorer is freely available as open-source software at https://github.com/Amirtesh/Pose-Rescorer . Post-docking rescoring MM/GBSA Single-frame energy evaluation Virtual Screening Reproducibility Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryPoseRescorerv1.1.1.zip 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. 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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-9125641","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":613288023,"identity":"a8fb8f9e-81eb-4697-8829-60c0f993b456","order_by":0,"name":"Amirtesh Raghuram","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYFACxgYQmcDPzMD+4QOQxcZOjJYDQC2S7QxsjDNAWpiJsQikxeA8UDEPiEdIC/+0w22fP1TU5TEcZmB7bPNrmzwfMwPjh485uLVI3E5snnHgzOFixmYGduPcvtuGbcwMzJIzt+GxBqiF4WDbgcRmoHukc3tuMwK1sDHz4tEiD9byry6xDaTFsue2PUEtBmAtDcyJPUCV0gw/bicS1GII0nLm2OHEGcyMzYa9DbeT24AMvH6Ru53+mKGipi5x//nDBx/8+HPbdn5788EPH/F5HwGAccrYBmWQAP6QongUjIJRMApGCgAA6slSoIu7xDkAAAAASUVORK5CYII=","orcid":"","institution":"Vellore Institute of Technology University","correspondingAuthor":true,"prefix":"","firstName":"Amirtesh","middleName":"","lastName":"Raghuram","suffix":""}],"badges":[],"createdAt":"2026-03-15 01:38:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9125641/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9125641/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105726056,"identity":"c3c7d86d-a219-4b70-80e3-704520f9c9b4","added_by":"auto","created_at":"2026-03-30 10:27:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":497786,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9125641/v1_covered_ec4675cf-5f56-4497-8ec7-0756a1674093.pdf"},{"id":105725915,"identity":"6206ce91-da3e-41d6-80cd-b0a111375ef8","added_by":"auto","created_at":"2026-03-30 10:26:42","extension":"zip","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":288158521,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryPoseRescorerv1.1.1.zip","url":"https://assets-eu.researchsquare.com/files/rs-9125641/v1/fc4e0ab90ab208979219c4ca.zip"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pose-Rescorer: A Deterministic Single-Frame MM/GBSA Workflow for Post-Docking Ligand Ranking","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"Post-docking rescoring, MM/GBSA, Single-frame energy evaluation, Virtual Screening, Reproducibility","lastPublishedDoi":"10.21203/rs.3.rs-9125641/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9125641/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Molecular docking is widely used for large-scale virtual screening, yet its empirical scoring functions are approximate and often fail to capture the balance between intermolecular interactions and solvation. 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