Computational investigation to identify potent inhibitors of the GTPase-Kirsten RAt sarcoma virus (K-Ras) mutants G12C and G12D.

K-Ras mutations are frequent in various cancer types, and according to recent research, K-Ras possesses four-drug targeting sites. This increased our interest in finding potential small molecule inhibitors with anticancer activity to treat K-Ras-driven cancers. We utilized integrated bioinformatic strategies, such as XP docking, MM-GBSA, cell-line cytotoxicity prediction, ADMET, and molecular simulation, to discover potential inhibitors of G12C and G12D mutants compared to sotorasib, which is a recent FDA-approved inhibitor of G12C. We identified compounds, such as flupentixol, amlodipine, and fluvoxamine, for the G12C mutant and paroxetine, flupentixol, and zuclopenthixol for the G12D mutant with significant inhibitory functions. All five compounds bound to the H95 cryptic groove of mutant K-Ras with high efficiency and, like sotorasib, retained a novel binding mechanism with additional hydrophobic interactions at the molecular level. Furthermore, the simulation studies suggested that the binding of flupentixol and amlodipine to G12C stabilizes switch I and switch II. In contrast, paroxetine and flupentixol to G12D showed a similar trend compared to sotorasib complexes. Thus, despite the very dynamic functionality of K-Ras switches I and II, the binding of shortlisted compounds is highly stable. Therefore, the reported study provides potential drug candidates for K-Ras inhibition that can be further developed with in vitro and in vivo evidence for targeted therapy.