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Article

The Se–S Bond Formation in the Covalent Inhibition Mechanism of SARS-CoV-2 Main Protease by Ebselen-like Inhibitors: A Computational Study

1
Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via Pietro Bucci, 87036 Arcavacata di Rende, CS, Italy
2
Institut de Chimie Physique UMR8000, Université Paris-Saclay, CNRS, 91405 Orsay, France
*
Author to whom correspondence should be addressed.
Academic Editor: József Tőzsér
Int. J. Mol. Sci. 2021, 22(18), 9792; https://doi.org/10.3390/ijms22189792
Received: 12 August 2021 / Revised: 3 September 2021 / Accepted: 7 September 2021 / Published: 10 September 2021
(This article belongs to the Special Issue Enzymes as Targets for Drug Development 2020)
The inhibition mechanism of the main protease (Mpro) of SARS-CoV-2 by ebselen (EBS) and its analog with a hydroxyl group at position 2 of the benzisoselenazol-3(2H)-one ring (EBS-OH) was studied by using a density functional level of theory. Preliminary molecular dynamics simulations on the apo form of Mpro were performed taking into account both the hydrogen donor and acceptor natures of the Nδ and Nε of His41, a member of the catalytic dyad. The potential energy surfaces for the formation of the Se–S covalent bond mediated by EBS and EBS-OH on Mpro are discussed in detail. The EBS-OH shows a distinctive behavior with respect to EBS in the formation of the noncovalent complex. Due to the presence of canonical H-bonds and noncanonical ones involving less electronegative atoms, such as sulfur and selenium, the influence on the energy barriers and reaction energy of the Minnesota hybrid meta-GGA functionals M06, M06-2X and M08HX, and the more recent range-separated hybrid functional wB97X were also considered. The knowledge of the inhibition mechanism of Mpro by the small protease inhibitors EBS or EBS-OH can enlarge the possibilities for designing more potent and selective inhibitor-based drugs to be used in combination with other antiviral therapies. View Full-Text
Keywords: SARS-CoV-2 main protease; DFT; inhibition mechanism; Se–S covalent bond; potential energy surface SARS-CoV-2 main protease; DFT; inhibition mechanism; Se–S covalent bond; potential energy surface
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MDPI and ACS Style

Parise, A.; Romeo, I.; Russo, N.; Marino, T. The Se–S Bond Formation in the Covalent Inhibition Mechanism of SARS-CoV-2 Main Protease by Ebselen-like Inhibitors: A Computational Study. Int. J. Mol. Sci. 2021, 22, 9792. https://doi.org/10.3390/ijms22189792

AMA Style

Parise A, Romeo I, Russo N, Marino T. The Se–S Bond Formation in the Covalent Inhibition Mechanism of SARS-CoV-2 Main Protease by Ebselen-like Inhibitors: A Computational Study. International Journal of Molecular Sciences. 2021; 22(18):9792. https://doi.org/10.3390/ijms22189792

Chicago/Turabian Style

Parise, Angela, Isabella Romeo, Nino Russo, and Tiziana Marino. 2021. "The Se–S Bond Formation in the Covalent Inhibition Mechanism of SARS-CoV-2 Main Protease by Ebselen-like Inhibitors: A Computational Study" International Journal of Molecular Sciences 22, no. 18: 9792. https://doi.org/10.3390/ijms22189792

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