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Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease.
Hognon, Cécilia; Marazzi, Marco; García-Iriepa, Cristina.
  • Hognon C; Grupo de Reactividad y Estructura Molecular (RESMOL), Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, Alcalá de Henares, 28801 Madrid, Spain.
  • Marazzi M; Grupo de Reactividad y Estructura Molecular (RESMOL), Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, Alcalá de Henares, 28801 Madrid, Spain.
  • García-Iriepa C; Instituto de Investigación Química "Andrés M. del Río" (IQAR), Universidad de Alcalá, Alcalá de Henares, 28801 Madrid, Spain.
Int J Mol Sci ; 23(10)2022 May 23.
Article in English | MEDLINE | ID: covidwho-1934115
ABSTRACT
Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys111), through a Michael addition reaction. An inhibition mechanism can therefore be proposed, including four

steps:

(i) ligand entry into the protease pocket; (ii) Cys111 deprotonation of the thiol group by a Brønsted-Lowry base; (iii) Cys111-S- addition to the ligand; and (iv) proton transfer from the protonated base to the covalently bound ligand. Evaluating the energetics and PLpro conformational changes at each of these steps could aid the design of more efficient and selective covalent inhibitors. For this aim, we have studied by means of MD simulations and QM/MM calculations the whole mechanism. Regarding the first step, we show that the inhibitor entry in the PLpro pocket is thermodynamically favorable only when considering the neutral Cys111, that is, prior to the Cys111 deprotonation. For the second step, MD simulations revealed that His272 would deprotonate Cys111 after overcoming an energy barrier of ca. 32 kcal/mol (at the QM/MM level), but implying a decrease of the inhibitor stability inside the protease pocket. This information points to a reversible Cys111 deprotonation, whose equilibrium is largely shifted toward the neutral Cys111 form. Although thermodynamically disfavored, if Cys111 is deprotonated in close proximity to the vinylic carbon of the ligand, then covalent binding takes place in an irreversible way (third step) to form the enolate intermediate. Finally, due to Cys111-S- negative charge redistribution over the bound ligand, proton transfer from the initially protonated His272 is favored, finally leading to an irreversibly modified Cys111 and a restored His272. These results elucidate the selectivity of Cys111 to enable formation of a covalent bond, even if a weak proton acceptor is available, as His272.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protons / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23105855

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protons / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23105855