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 |
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| Authors: | Kemel Arafet,Natalia Serrano-Aparicio,Alessio Lodola,Adrian J. Mulholland,Florenci V. Gonzá lez,Katarzyna Ś widerek,Vicent Moliner |
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| Affiliation: | Departament de Química Física i Analítica, Universitat Jaume I, 12071 Castelló Spain.; Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Italy ; Centre for Computational Chemistry, School of Chemistry, University of Bristol, UK ; Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12071 Castelló Spain |
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| Abstract: | 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.QM/MM simulations identify the mechanism of reaction of N3, a covalent peptidyl inhibitor of SARS-CoV-2 main protease. Modelling of two novel proposed compounds, B1 and B2, suggests that reversibility of covalent inhibition could be tailored. |
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