Abstract
KRAS, a key member of the Ras family of GTPases, plays a crucial role in regulating cell growth, survival, and differentiation. Mutations in KRAS, such as G12R, are frequently linked to cancer, making it an important therapeutic target. Due to its smooth surface and strong nucleotide-binding affinity, KRAS has long been considered difficult to target with drugs. Recent advancements have identified new binding sites, including allosteric pockets and the Switch-I/Switch-II (SI/II) regions, which offer alternative strategies for drug development. In this study, a combination of computational techniques was used to identify potential inhibitors of KRAS and its G12R mutant. Virtual screening revealed four promising compounds NSC 374,037, NSC 655,101, V016-9984, and N060-0122 that outperformed known inhibitors such as Sotorasib in binding affinity. Molecular dynamics simulations confirmed the stability of these compounds within KRAS binding pockets, supported by favourable RMSD, RMSF, and radius of gyration values. Binding energy calculations showed that NSC 655,101 had the strongest affinity for wild-type KRAS while V016-9984 and N060-0122 were most effective at targeting the allosteric and SI/II sites respectively. Time-lagged Independent Component Analysis (TICA) provided critical insights into how these ligands modulate KRAS conformational dynamics, revealing ligand-specific effects on protein flexibility and stabilization of key conformations. These findings highlight the potential of these inhibitors as promising candidates for KRAS-targeted therapies. The results provide a strong basis for further experimental testing, bringing us closer to effective treatments for KRAS-driven cancers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00415-4.