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Mechanism of Inhibition of SARS-CoV-2 Mpro by N3 Peptidyl Michael Acceptor Explained by QM/MM Simulations and Design of New Derivatives with Tunable Chemical Reactivity

preprint
submitted on 11.09.2020 and posted on 11.09.2020 by Kemel Arafet, Natalia Serrano-Aparicio, Alessio Lodola, Adrian Mulholland, Florenci V. González, Katarzyna Swiderek, Vicent Moliner
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 Mpro with 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 accessible N3-analogues as potential inhibitors, in which the recognition and warhead motifs are modified. QM/MM modelling of the mechanism of inhibition of Mpro by 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.

Funding

Spanish Ministerio de Ciencia, Innovación y Universidades

Generalitat Valenciana

Universitat Jaume I

Pirineus and Barcelona Supercomputing Center

EPSRC

British Society for Antimicrobial Chemotherapy

History

Email Address of Submitting Author

moliner@uji.es

Institution

Universitat Jaume I

Country

Spain

ORCID For Submitting Author

0000-0002-7528-1551

Declaration of Conflict of Interest

no conflict of interests

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