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

Abstract

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. Author SummaryMutation-induced resistance is a common challenge across many cancer types and is often associated with aggressive tumor progression and poor therapeutic response. Investigating the dynamic properties of proteins harboring such mutations provides valuable insights into the structural and functional consequences of these alterations, thereby helping to elucidate the mechanisms of drug resistance. Machine learning algorithms are particularly effective at uncovering complex patterns within high-dimensional data, such as molecular dynamics simulation trajectories. Integrating these algorithms with analysis of protein dynamics holds significant potential to aid in drug discovery challenges by reducing both time and resource demands while increasing the likelihood of identifying effective therapeutic candidates. As a proof of concept, we developed a computational framework that integrates molecular dynamics-derived molecular features with machine learning to distinguish treatment-sensitive from treatment-resistant KRAS mutants. KRAS is known for drug resistance arising from secondary mutations that disrupt inhibitor binding despite intact covalent attachment sites. The models achieved over 90% accuracy and identified solvent-exposure and conformational changes at residues G10, E62, and H95 as key predictors of treatment resistance. This workflow offers a generalizable strategy for understanding and forecasting mutation-induced resistance.