Vivek Dhar Dwivedi, Mohd Saeed, Mohammad Amjad Kamal
KRAS is a major oncogenic target in precision oncology because of its conformational flexibility and limited druggability. This study employed an integrated multiscale computational strategy to identify and characterize novel KRAS inhibitors with improved structural, thermodynamic, and electronic stability. Virtual screening and molecular docking identified three promising compounds, F3409-0029, F6725-0291, and F3408-0006, with strong affinity for the KRAS active site. To assess conformational stability and ligand adaptability, we performed 500 ns molecular dynamics simulations for all complexes. Among them, the KRAS-F3408-0006 complex showed the highest structural stability, as reflected in stable RMSD values, reduced residue fluctuations, compact conformational behavior, and sustained ligand accommodation throughout the trajectory. MM/GBSA calculations revealed favorable binding energetics dominated by van der Waals and electrostatic interactions. Per-residue MM/GBSA decomposition also identified key energetic hotspots that contribute to F3408-0006 binding to KRAS. Principal component analysis and free energy landscape profiling further showed restricted collective motions and a dominant low-energy conformational basin, supporting greater thermodynamic stability than the reference inhibitor. Density functional theory and QM/MM analyses additionally confirmed favorable frontier molecular orbital distribution and stable quantum-level interactions within the binding cavity. Overall, F3408-0006 emerged as a promising KRAS inhibitor candidate for future experimental validation.