Assessing Lysine and Cysteine Reactivities for Designing Targeted Covalent Kinase Inhibitors.

ABSTRACT: Targeted covalent inhibitor design is gaining increasing interest and acceptance. A typical covalent kinase inhibitor design targets a reactive cysteine; however, this strategy is limited by the low abundance of cysteine and acquired drug resistance from point mutations. Inspired by the recent development of lysine-targeted chemical probes, we asked if nucleophilic (reactive) catalytic lysines are common on the basis of the published crystal structures of the human kinome. Using a newly developed p K_a prediction tool based on continuous constant pH molecular dynamics, the catalytic lysines of eight unique kinases from various human kinase groups were retrospectively and prospectively predicted to be nucleophilic, when kinase is in the rare DFG-out/αC-out type of conformation. Im

SUBMITTER: Liu R 

PROVIDER: S-EPMC6935298 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature