Integrating computational chemistry and machine learning to predict KRAS mutation-induced resistance.

Mutation-induced drug resistance is a major contributor to the failure of targeted cancer therapies, particularly in tumors driven by mutations in the KRAS oncogene. Although covalent inhibitors effectively target KRAS G12C, secondary mutations such as G12C/Y96C, G12C/Y96S, and G12C/Y96D lead to resistance despite leaving the covalent attachment site intact. To predict these resistance outcomes, we developed a computational framework that integrates molecular dynamics-derived structural, energetic, thermodynamic, and contact-based descriptors with machine learning. Features extracted from simulations of treatment-sensitive and treatment-resistant KRAS mutants were used to train logistic regression, random forest, support vector machine, and Bayesian Network classifiers, achieving average accuracies above 90%. Solvent-accessible surface area variability, Lennard-Jones 1,4 energy, mean square displacement, and root mean square fluctuation emerged as the most discriminatory features. Residues G10, E62, and H95 showed the highest predictive value. This approach highlights conformational and solvent-exposure changes as central drivers of KRAS drug resistance and provides a generalizable workflow for other clinically relevant mutant targets.