Polarizable MD and QM/MM investigation of acrylamide-based leads to target the main protease of SARS-CoV-2.

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme for the replication of the virus causing the COVID-19 pandemic. Because there is no known homologue in humans, it has been proposed as a primary target for antiviral drug development. Here, we explore the potential of five acrylamide-based molecules as possible covalent inhibitors, leading to target MPro by docking, followed by polarizable molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. All calculations involving a classical potential were calculated with the AMOEBABIO18 polarizable force field, while electronic structure calculations were performed within the framework of density functional theory. Selected docking poses for each of the five compounds were used for MD simulations, which suggest only one of the tested leads remains bound in a catalytically active orientation. The QM/MM results for the covalent attachment of the promising lead to the catalytic serine suggest that this process is thermodynamically feasible but kinetically unlikely. Overall, our results are consistent with the low labeling percentages determined experimentally and may be useful for further development of acrylamide-based leads.

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

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 âˆ¼11,000 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 Mpro reversible inhibitor led to an acrylamide inhibitor series with low micromolar IC50 values against SARS-CoV-2 Mpro. The docking was validated by 12 co-crystal structures. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.