Impact of Warhead Modulations on the Covalent Inhibition of SARS-CoV-2 M pro Explored by QM/MM Simulations.

Sergio Martí, Kemel Arafet, Alessio Lodola, Adrian J Mulholland, Katarzyna Świderek, Vicent Moliner

Research output: Contribution to journalArticle (Academic Journal)peer-review

18 Citations (Scopus)

Abstract

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, shows the need for effective antiviral treatments. Here, we present a simulation study of the inhibition of the SARS-CoV-2 main protease (M pro), a cysteine hydrolase essential for the life cycle of the virus. The free energy landscape for the mechanism of the inhibition process is explored by QM/MM umbrella sampling and free energy perturbation simulations at the M06-2X/MM level of theory for two proposed peptidyl covalent inhibitors that share the same recognition motif but feature distinct cysteine-targeting warheads. Regardless of the intrinsic reactivity of the modeled inhibitors, namely a Michael acceptor and a hydroxymethyl ketone activated carbonyl, our results confirm that the inhibitory process takes place by means of a two-step mechanism, in which the formation of an ion pair C145/H41 dyad precedes the protein-inhibitor covalent bond formation. The nature of this second step is strongly dependent on the functional groups in the warhead: while the nucleophilic attack of the C145 sulfur atom on the Cα of the double bond of the Michael acceptor takes place concertedly with the proton transfer from H41 to C β, in the compound with an activated carbonyl, the sulfur attacks the carbonyl carbon concomitant with a proton transfer from H41 to the carbonyl oxygen via the hydroxyl group. An analysis of the free energy profiles, structures along the reaction path, and interactions between the inhibitors and the different pockets of the active site on the protein shows a measurable effect of the warhead on the kinetics and thermodynamics of the process. These results and QM/MM methods can be used as a guide to select warheads to design efficient irreversible and reversible inhibitors of SARS-CoV-2 M pro.

Original languageEnglish
Pages (from-to)698-708
Number of pages11
JournalACS Catalysis
Volume12
Issue number1
DOIs
Publication statusPublished - 7 Jan 2022

Bibliographical note

Funding Information:
This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (Grant PGC2018-094852–B-C21 and PID2019-107098RJ-I00), the Generalitat Valenciana (Grant AICO/2019/195 and SEJI/2020/007), and Universitat Jaume I (UJI-A2019-04 and UJI-B2020-03). K.A. thanks the Generalitat Valenciana (APOSTD/2020/015) for a postdoctoral contract. The authors acknowledge the computer resources at Mare Nostrum of the Barcelona Supercomputing Center (QSB-2021-1-0007), as well as the local computational resources of the Servei d’Informàtica of Universitat Jaume I. A.J.M. thanks the EPSRC for support (CCP-BioSim, grant number EP/M022609/1).

Funding Information:
This work was supported by the Spanish Ministerio de Ciencia, Innovacio?n y Universidades (Grant PGC2018-094852?B-C21 and PID2019-107098RJ-I00), the Generalitat Valenciana (Grant AICO/2019/195 and SEJI/2020/007), and Universitat Jaume I (UJI-A2019-04 and UJI-B2020-03). K.A. thanks the Generalitat Valenciana (APOSTD/2020/015) for a postdoctoral contract. The authors acknowledge the computer resources at Mare Nostrum of the Barcelona Supercomputing Center (QSB-2021-1-0007), as well as the local computational resources of the Servei d?Informa?tica of Universitat Jaume I. A.J.M. thanks the EPSRC for support (CCP-BioSim, grant number EP/M022609/1).

Publisher Copyright:
© 2021 American Chemical Society

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