Unveiling Novel KRAS G12V Inhibitors: A Comprehensive Study Using Computer-aided Drug Design Approach

Abstract

The KRAS G12V mutation is a formidable oncogenic driver implicated in the pathogenesis of several aggressive cancers, including pancreatic ductal adenocarcinoma, non-small cell lung cancer, and colorectal cancer. Overcoming the historical challenges associated with targeting KRAS mutations, this study harnesses advanced computer-aided drug design (CADD) techniques to unearth novel and potent inhibitors. By leveraging the structural paradigms of clinically validated KRAS inhibitors sotorasib and adagrasib, we systematically screened the PubChem database, yielding 628 promising candidates. Molecular docking simulations pinpointed three standout compounds: CID_138637935, CID_155344829, and CID_165158764, distinguished by their exceptional binding affinities. Subsequent molecular dynamics (MD) simulations offered an in-depth exploration of these compounds, revealing CID_155344829 as the frontrunner, with unparalleled stability, and compact structural integrity. While CID_138637935 and CID_165158764 displayed notable potential, further refinement is warranted. Our findings illuminate the transformative potential of CADD in revolutionizing cancer therapeutics and lay the groundwork for future in vitro and in vivo investigations to validate and optimize these novel KRAS G12V inhibitors.