Structure-Based Prediction of Kinase Activation amidst a Varied Mutational Landscape Using Privileged Learning

Post-translational modifications such as phosphorylation catalyzed by kinases are essential for cell signaling. The activation of mutated kinase in a cancer cell can profoundly impact disease progression and drug efficacy. However, numerous clinical mutations in the human kinome impose challenges in defining the quantitative structure-activity relationship. Previous work (Patil K. et al. PNAS 2021, 118(10), e2019132118.) shows that perturbation of structural properties such as hydrogen-bonding occupancy in the áC-helix and the activation loop domains computed from molecular dynamics (MD) simulation is a good indicator of the activation status of anaplastic ymphoma kinase (ALK) mutants with 2/3rd of the mutants utilizing this mechanism of activation.