Összes szerző

Mahdi Mohamed

az alábbi absztraktok szerzői között szerepel:

Hoffka Gyula
Multiscale computational study on the binding of nirmatrelvir to SARS-CoV-2 main protease: possible pathways to resistance

Aug 29 - kedd

10:00 – 10:15

Molekuláris biofizika

E06

Multiscale computational study on the binding of nirmatrelvir to SARS-CoV-2 main protease: possible pathways to resistance

Gyula Hoffka1,2, Mohamed Mahdi1, József Tőzsér1 and János András Mótyán1

1 University of Debrecen, Faculty of Medicine, Department of Biochemistry and Molecular Biology, Laboratory of Retroviral Biochemistry

2 University of Debrecen, Doctoral School of Molecular Cell and Immune Biology

The pandemic caused by SARS-CoV-2 has resulted in millions of infections worldwide. Multiple vaccination strategies are available, but the number of the antivirals which are specific for SARS-CoV-2 is still limited. The Paxlovid is an antiviral combination that has been developed by Pfizer to treat non-hospitalized COVID-19 patients. It contains nirmatrelvir, a covalent inhibitor of the SARS-CoV-2 main protease (Mpro). Similar to the SARS-CoV-2 spike protein, the Mpro is also prone to mutations, which mutations may potentially interfere with binding of ligands, including nirmatrelvir, leading to the emergence of resistance.

In order to study the structural background of enzyme-inhibitor interactions, we examined the non-covalent interactions, as well as the reaction mechanism of SARS-CoV-2 Mpro with a peptide substrate and nirmatrelvir inhibitor. The interactions between the enzyme and the peptide substrate or nirmatrelvir were compared based on multiple crystal structures [1]. We mapped the crucial non-covalent interactions by applying molecular dynamics simulations for structural analyses. Mechanism of substrate cleavage and nirmatrelvir binding at atomic level were investigated by applying hybrid QM/MM ONIOM method. Previously described nirmatrelvir-resistant SARS-CoV-2 Mpro variants were also investigated to study the mechanism of resistance.

Our results contribute to a better understanding of the molecular mechanism underlying the substrate cleavage and nirmatrelvir binding. Based on a comprehensive analysis of our computational simulations, we propose how individual mutations of the active site may contribute to resistance development.

This work was supported in part by TKP2021-EGA-20 (Biotechnology) and POST-COVID2021-16 projects. We acknowledge KIFÜ for awarding us access to resource based in Hungary.

[1] Mótyán JA, Mahdi M, Hoffka G, Tőzsér J (2022) Int J Mol Sci 23:3507