In-silico study to identify a potential KRAS G12D targeting compound using MRTX1133 as the lead molecule

Mutations in the RAS oncogene are prevalent in a wide range of human cancers. Among the RAS family, KRAS is the most frequently mutated, with the G12D variant being particularly common. The KRAS G12D mutation impairs intrinsic GTPase activity, locking KRAS in a constitutively active state that drives persistent downstream signaling and uncontrolled cellular proliferation. Targeting this mutation with selective inhibitors therefore represents an important therapeutic strategy. In this study, a ligand-based pharmacophore model was generated from the experimentally validated KRAS G12D inhibitor MRTX1133. The validated pharmacophore model was used to screen for potential inhibitors, followed by ADME evaluation and molecular docking. Among the identified compounds, ZINC73760428(Z1), ZINC72128180(Z3), and ZINC13012000(Z4) exhibited favorable binding affinities together with favorable computationally predicted physicochemical, pharmacokinetic, and drug-like properties. All atom molecular dynamics simulations demonstrated stable binding of Z1 to KRAS G12D. Comparative analyses with wild-type KRAS further showed reduced binding stability of Z1, suggesting preferential interaction with the mutant protein. MM/PBSA binding free-energy calculations and hydrogen-bond analyses further supported the stable interaction of Z1 with KRAS G12D. Overall, the integrated computational workflow identified ZINC73760428(Z1) as a potential KRAS G12D-selective lead compound for further investigation.