The SARS-CoV-2 main protease (Mpro) 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 Mprowith a known Michael acceptor (peptidyl) inhibitor,N3. The free energy landscape for the mechanism of the formation of the covalent enzyme-inhibitor product is computed with QM/MM molecular dynamics methods. The simulations show a two-step mechanism, and give structures and calculated barriers in good agreement with experiment. Using these results and information from our previous investigation on the proteolysis reaction of SARS-CoV-2 Mpro, we design two new, synthetically accessibleN3-analogues as potential inhibitors, in which the recognition and warhead motifs are modified. QM/MM modelling of the mechanism of inhibition of Mproby these novel compounds indicates that both may be promising candidates as drug leads against COVID-19, one as an irreversible inhibitor and one as a potential reversible inhibitor.
Mechanism of inhibition of SARS-CoV-2 MprobyN3peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity / Arafet, K.; Serrano-Aparicio, N.; Lodola, A.; Mulholland, A. J.; Gonzalez, F. V.; Swiderek, K.; Moliner, V.. - In: CHEMICAL SCIENCE. - ISSN 2041-6520. - 12:4(2021), pp. 1433-1444. [10.1039/d0sc06195f]