An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro 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 existing SARS-CoV M^pro reversible inhibitor led to an acrylamide inhibitor series with low micromolar IC₅₀ values against SARS-CoV-2 M^pro. The docking was validated by 12 co-crystal structures. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.

Keywords: COVID-19; DOCKovalent; M(pro); SARS-CoV-2; computer-aided drug discovery; covalent docking; covalent inhibitors; irreversible inhibitors.