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

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2021 Jun 24

PMID 34163906

Citations 51

Authors

Kemel Arafet

Natalia Serrano-Aparicio

Alessio Lodola

Adrian J Mulholland

Florenci V Gonzalez

Katarzyna Swiderek

Vicent Moliner

Affiliations

Soon will be listed here.

Abstract

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. 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 M, we design two new, synthetically accessible -analogues as potential inhibitors, in which the recognition and warhead motifs are modified. QM/MM modelling of the mechanism of inhibition of M 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.

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