Enhanced sampling and ligandability assessment to expand the repertoire of potentially druggable cryptic pockets

Enhanced sampling and ligandability assessment to expand the repertoire of potentially druggable cryptic pockets | 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 Enhanced sampling and ligandability assessment to expand the repertoire of potentially druggable cryptic pockets Neha Vithani, She Zhang, Judith Günther, Hans Purkey, J. David Lawson, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8854093/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 Certain proteins known to be involved in life-threatening diseases remained challenging therapeutic targets for decades simply because a suitable binding pocket for a potent molecular inhibitor could not be identified in their ground state apo structures. In the last decade, discovery of cryptic pockets in challenging targets like KRAS and Werner helicase has proven to be a major turning point for therapeutic development. However, the alternate protein conformations required for these cryptic pockets to exist were only revealed by experiments conducted in the presence of ligands that can bind to them. Time-consuming and expensive experiments currently used to uncover these biologically rare events could be usefully complemented by a computational method capable of reliably identifying cryptic pockets. We have previously shown that aqueous and mixed-solvent Weighted Ensemble molecular dynamics (WEMD) simulations driven by normal modes representing the direction of the most-collective motion of a protein can predict known cryptic pockets in the KRAS oncoprotein. Here, we evaluate this cryptic pocket detection technique on a dataset of diverse proteins and show that it successfully identifies cryptic pockets over 92% of the time starting with just the apo structure. We also show that we can successfully rank candidate pockets from WEMD using our pocket ligandability prediction model, Target X. Computational Biology Computational Chemistry Drug Discovery, Design, & Development cryptic pockets molecular dynamics weighted ensemble druggability mixed-solvent Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SIcpdvalidation.docx Supplementary Information File 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-8854093","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":589779961,"identity":"efb11ff3-75c1-4cc1-9f2b-7f4d034d2fbf","order_by":0,"name":"Neha Vithani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYDACZgY2ICnBwA8midPCDNEi2UC0FgawFgYGgwPEajE4zn/swc8dFnnGxw8/vPFxh50cA/vhoxvwajnMzG7Ye0ai2OxMmrHlzDPJxgw8aWk38GmRbGZmk+Btk0jcdoPBTJq37UBigwSPGUEtkn+BWjbPYP8m/bftQD1BLfzAEJMG2bIBqFKase1AAgMRWsykZYFaZpzJKbbsbUs2bCPkFzb+g88k37bVJfa3H99442ebnTw/++FjeLVgMYQ05aNgFIyCUTAKsAEA3AtBHUO70+wAAAAASUVORK5CYII=","orcid":"","institution":"OpenEye, Cadence Molecular Sciences","correspondingAuthor":true,"prefix":"","firstName":"Neha","middleName":"","lastName":"Vithani","suffix":""},{"id":589779962,"identity":"316a54f6-208a-4954-b042-cc2e512f23fd","order_by":1,"name":"She Zhang","email":"","orcid":"","institution":"OpenEye, Cadence Molecular Sciences","correspondingAuthor":false,"prefix":"","firstName":"She","middleName":"","lastName":"Zhang","suffix":""},{"id":589779963,"identity":"b56c9d8f-1302-459a-af7f-36f2feed391d","order_by":2,"name":"Judith Günther","email":"","orcid":"","institution":"Bayer AG, Drug Discovery Sciences","correspondingAuthor":false,"prefix":"","firstName":"Judith","middleName":"","lastName":"Günther","suffix":""},{"id":589779964,"identity":"ac0aaacb-e4d5-432a-916e-2f5827aee9b8","order_by":3,"name":"Hans Purkey","email":"","orcid":"","institution":"Genentech, Inc.","correspondingAuthor":false,"prefix":"","firstName":"Hans","middleName":"","lastName":"Purkey","suffix":""},{"id":589779965,"identity":"9f05b089-07fb-405f-a515-7aee85650690","order_by":4,"name":"J. 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