Exploring the conformational space of ROS1 kinase domain and the impact of allosteric mutations.

Chromosomal rearrangements are common oncogenic events in Non-Small Cell Lung Cancer. An example is the fusion of the ROS1 kinase domain with extracellular receptors. Although the fusion leads to a target that is druggable with multi-kinase inhibitors, several reports indicate the emergence of point mutations leading to drug resistance. Although these mutations are often located in the ATP binding pocket, a subset of them is neighboring the pocket without a direct effect on drug binding. Due to the clinical impact of these allosteric mutations, there is an urge to identify the mechanism of resistance and characterize the pocket for further drug design studies. This study aimed to unravel the resistance mechanism of L1982F and S1986F/Y mutations. The variants were modeled and simulated using classical Molecular Dynamics simulations and accessed for their conformational flexibility. Our results indicate a direct effect of these allosteric mutants in the binding pocket volume with an indication of the G-loop playing a central role.