Exploring MERTK inhibitor binding mechanisms: insights from adaptive steered molecular dynamics and free energy calculation

MERTK, a promising drug target for the treatment of human leukemia and solid tumors, and the development of its small molecule inhibitors holds significant clinical potential. However, the underlying reasons for the varying activities among these inhibitors and the specifics of their binding mechanism have not been systematically investigated. By combining conventional molecular dynamics simulations, adaptive steered molecular dynamics simulations and binding free energy calculations based on molecular mechanics Poisson–Boltzmann surface area, the interaction modes of four MERTK inhibitors and dissociation behavior are discussed in detail. The results reveal additional critical amino acids, beyond the well-known hot spot residues in the kinase hinge region, that play a pivotal role in inhibitor binding. Our findings further indicate that the binding of MERTK to its inhibitors relies not only on crucial hydrogen bonding interactions but also benefits from non-polar interactions. In addition, the analysis of hydrogen bonding within kinetic trajectories and potential of mean force explained the differences in activity between different inhibitors, providing insights for the design and optimization of subsequent MERTK-targeted small molecule inhibitors.