High-Throughput Screening and Quantum Mechanics for Identifying Potent Inhibitors Against Mac1 Domain of SARS-CoV-2 Nsp3

0544596 - ÚOCHB 2022 RIV US eng J - Journal Article
Selvaraj, C. - Dinesh, Dhurvas Chandrasekaran - Panwar, U. - Bouřa, Evžen - Singh, S. K.
High-Throughput Screening and Quantum Mechanics for Identifying Potent Inhibitors Against Mac1 Domain of SARS-CoV-2 Nsp3.
I E E E - A C M Transactions on Computational Biology and Bioinformatics. Roč. 18, č. 4 (2021), s. 1262-1270. ISSN 1545-5963. E-ISSN 1557-9964
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Grant - others:AV ČR(CZ) L200551951
Institutional support: RVO:61388963
Keywords : COVID-19 * Mac1 * Macro X * molecular dynamics * Nsp3 * quantum mechanics * SARS-CoV-2
OECD category: Biochemical research methods
Impact factor: 3.702, year: 2021
Method of publishing: Limited access
https://doi.org/10.1109/TCBB.2020.3037136

SARS-CoV-2 encodes the Mac1 domain within the large nonstructural protein 3 (Nsp3), which has an ADP-ribosylhydrolase activity conserved in other coronaviruses. The enzymatic activity of Mac1 makes it an essential virulence factor for the pathogenicity of coronavirus (CoV). They have a regulatory role in counteracting host-mediated antiviral ADP-ribosylation, which is unique part of host response towards viral infections. Mac1 shows highly conserved residues in the binding pocket for the mono and poly ADP-ribose. Therefore, SARS-CoV-2 Mac1 enzyme is considered as an ideal drug target and inhibitors developed against them can possess a broad antiviral activity against CoV. ADP-ribose-1 phosphate bound closed form of Mac1 domain is considered for screening with large database of ZINC. XP docking and QPLD provides strong potential lead compounds, that perfectly fits inside the binding pocket. Quantum mechanical studies expose that, substrate and leads have similar electron donor ability in the head regions, that allocates tight binding inside the substrate-binding pocket. Molecular dynamics study confirms the substrate and new lead molecules presence of electron donor and acceptor makes the interactions tight inside the binding pocket. Overall binding phenomenon shows both substrate and lead molecules are well-adopt to bind with similar binding mode inside the closed form of Mac1.
Permanent Link: http://hdl.handle.net/11104/0321439