Profiling MAP kinase cysteines for targeted covalent inhibitor design.

ABSTRACT: Mitogen-activated protein kinases (MAPK) are important therapeutic targets, and yet no inhibitors have advanced to the market. Here we applied the GPU-accelerated continuous constant pH molecular dynamics (CpHMD) to calculate the pK _a's and profile the cysteine reactivities of all 14 MAPKs for assisting the targeted covalent inhibitor design. The simulations not only recapitulated but also rationalized the reactive cysteines in the front pocket of JNK1/2/3 and the extended front pocket of p38α. Interestingly, the DFG - 1 cysteine in the DFG-in conformation of ERK1/ERK2 was found somewhat reactive or unreactive; however, simulations of MKK7 showed that switching to the DFG-out conformation makes the DFG - 1 cysteine reactive, suggesting the advantage of type II covalent in

SUBMITTER: Liu R 

PROVIDER: S-EPMC8792824 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature