Inhibition mechanism of MRTX1133 on KRAS: a molecular dynamics simulation and Markov state model study.

The mutant KRAS was considered as an "undruggable" target for decades, especially KRAS. It is a great challenge to develop the inhibitors for KRAS which lacks the thiol group for covalently binding ligands. The discovery of MRTX1133 solved the dilemma. Interestingly, MRTX1133 can bind to both the inactive and active states of KRAS. The binding mechanism of MRTX1133 with KRAS, especially how MRTX1133 could bind the active state KRAS without triggering the active function of KRAS has not been fully understood. Here, we used a combination of all-atom molecular dynamics simulations and Markov state model (MSM) to understand the inhibition mechanism of MRTX1133 and its analogs. The stationary probabilities derived from MSM show that MRTX1133 and its analogs can stabilize the inactive or active states of KRAS into different conformations. More remarkably, by scrutinizing the conformational differences, MRTX1133 and its analogs were hydrogen bonded to Gly60 to stabilize the switch II region and left switch I region in a dynamically inactive conformation, thus achieving an inhibitory effect. Our simulation and analysis provide detailed inhibition mechanism of KRAS induced by MRTX1133 and its analogs. This study will provide guidance for future design of novel small molecule inhibitors of KRAS.