Mechanism of inhibition of SARS-CoV-2 M by peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity.

The SARS-CoV-2 main protease (M) is essential for replication of the virus responsible for the COVID-19 pandemic, and one of the main targets for drug design. Here, we simulate the inhibition process of SARS-CoV-2 M with a known Michael acceptor (peptidyl) inhibitor, . The free energy landscape for the mechanism of the formation of the covalent enzyme-inhibitor product is computed with QM/MM molecular dynamics methods.

Revealing the molecular mechanisms of proteolysis of SARS-CoV-2 M by QM/MM computational methods.

SARS-CoV-2 M is one of the enzymes essential for the replication process of the virus responsible for the COVID-19 pandemic. This work is focused on exploring its proteolysis reaction by means of QM/MM methods. The resulting free energy landscape of the process provides valuable information on the species appearing along the reaction path and suggests that the mechanism of action of this enzyme, taking place in four steps, slightly differs from that of other cysteine proteases.