Encounter complexes and hidden poses of kinaseinhibitor binding on the free-energy landscape

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Abstract

Modern drug discovery increasingly focuses on the drug-target binding kinetics which depend on drug (un)binding pathways. The conventional molecular dynamics simulation can observe only a few binding events even using the fastest supercomputer. Here, we develop 2D gREST/REUS simulation with enhanced flexibility of the ligand and the protein binding site. Simulation (43 μ s in total) applied to an inhibitor binding to c-Src kinase covers 100 binding and unbinding events. On the statistically converged free-energy landscapes, we succeed in predicting the X-ray binding structure, including water positions. Furthermore, we characterize hidden semibound poses and transient encounter complexes on the free-energy landscapes. Regulatory residues distant from the catalytic core are responsible for the initial inhibitor uptake and regulation of subsequent bindings, which was unresolved by experiments. Stabilizing/blocking of either the semibound poses or the encounter complexes can be an effective strategy to optimize drug-target residence time.

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Re, S., Oshima, H., Kasahara, K., Kamiya, M., & Sugita, Y. (2019). Encounter complexes and hidden poses of kinaseinhibitor binding on the free-energy landscape. Proceedings of the National Academy of Sciences of the United States of America, 116(37), 18404–18409. https://doi.org/10.1073/pnas.1904707116

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