Transfiguring Novel Marine Natural Product as oncogenic KRAS G12C Mutant Inhibitors via In-Silico and Computational Approaches

KRAS mutations cause a variety of malignancies, with the KRAS-G12C variation serving as a key oncogenic target. Despite the approval of Sotorasib for KRAS G12C-mutated NSCLC, resistance and poor efficacy indicate the need for new inhibitors. This study screened over 11,800 marine-derived chemicals from the CMNPD database using a computer-assisted workflow. Following drug-likeness filtering and virtual screening, three candidates (CMNPD27430, CMNPD23547, and CMNPD10958) demonstrated higher binding affinities to KRAS-G12C than Sotorasib. Molecular dynamics simulations (100 ns) confirmed complex stability, which was validated by RMSD, RMSF, Rg, SASA, and hydrogen bonding analysis. ADMET profiling also revealed favorable drug-like and pharmacokinetic characteristics. These findings suggest that marine natural compounds are viable scaffolds for the future development of KRAS-G12C inhibitors.