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.