An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M^pro inhibitor.

ABSTRACT: Designing covalent inhibitors is increasingly important, although it remains challenging. Here, we present covalentizer, a computational pipeline for identifying irreversible inhibitors based on structures of targets with non-covalent binders. Through covalent docking of tailored focused libraries, we identify candidates that can bind covalently to a nearby cysteine while preserving the interactions of the original molecule. We found ∼11,000 cysteines proximal to a ligand across 8,386 complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In a prospective evaluation, five out of nine predicted covalent kinase inhibitors showed half-maximal inhibitory concentration (IC₅₀) values between 155 nM and 4.5 μM. Application against an existin

SUBMITTER: Zaidman D 

PROVIDER: S-EPMC8228784 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature