Disentangling the nonbonding interaction energy between KRAS oncoproteins and small-molecule non-covalent inhibitors helps clarifying how inhibition occurs

Disentangling the nonbonding interaction energy between KRAS oncoproteins and small-molecule non-covalent inhibitors helps clarifying how inhibition occurs | 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 Disentangling the nonbonding interaction energy between KRAS oncoproteins and small-molecule non-covalent inhibitors helps clarifying how inhibition occurs Francesco Pietra This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7366644/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Nov, 2025 Read the published version in Medicinal Chemistry Research → Version 1 posted 4 You are reading this latest preprint version Abstract Modeling small-molecule non-covalent inhibitors of RAS oncoproteins has so far been carried out at whole molecule level, thereby leaving important molecular details hidden. Actually, for the endless process of improving the inhibitor performance, a more detailed knowledge of such interactions is desirable. The challenge of improving on that situation has been taken here by disentangling the energies of interaction of KRAS G12D mutant residues with non-covalent inhibitors that, such as of BI-2865 or MRTX1133, are currently on the limelight. The problem was addressed to molecular dynamics and quantum mechanics-molecular mechanics computer simulations in the lack of suitable experimental approaches. It emerged where, at atomic detail, the inhibitor sticks better. In addition, for ternary complexes, such as of the non-covalent inhibitor RCM-6236 with cyclophilin A and KRAS, indications are provided as to the mechanism of inhibition. Such detailed views may offer clues as to where a new generation of inhibitors can stick even better to the receptor, and of repulsive situations to avoid. Molecular dynamics Quantum mechanics-molecular mechanics KRAS non-covalent inhibitors - ternary KRAS complexes Full Text Additional Declarations No competing interests reported. Supplementary Files BI2865rtfprm.txt MRTX1133rtfprm.txt RCM6236.str Cite Share Download PDF Status: Published Journal Publication published 19 Nov, 2025 Read the published version in Medicinal Chemistry Research → Version 1 posted Editorial decision: Revision requested 14 Aug, 2025 Editor assigned by journal 14 Aug, 2025 Submission checks completed at journal 14 Aug, 2025 First submitted to journal 13 Aug, 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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