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High-Throughput Screening and Quantum Mechanics for Identifying Potent Inhibitors Against Mac1 Domain of SARS-CoV-2 Nsp3
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SYSNO ASEP 0544596 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title High-Throughput Screening and Quantum Mechanics for Identifying Potent Inhibitors Against Mac1 Domain of SARS-CoV-2 Nsp3 Author(s) Selvaraj, C. (IN)
Dinesh, Dhurvas Chandrasekaran (UOCHB-X) ORCID
Panwar, U. (IN)
Bouřa, Evžen (UOCHB-X) ORCID
Singh, S. K. (IN)Source Title I E E E - A C M Transactions on Computational Biology and Bioinformatics. - : Association for Computing Machinery - ISSN 1545-5963
Roč. 18, č. 4 (2021), s. 1262-1270Number of pages 9 s. Language eng - English Country US - United States Keywords COVID-19 ; Mac1 ; Macro X ; molecular dynamics ; Nsp3 ; quantum mechanics ; SARS-CoV-2 OECD category Biochemical research methods R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000682137300006 EID SCOPUS 85097955294 DOI 10.1109/TCBB.2020.3037136 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2022 Electronic address https://doi.org/10.1109/TCBB.2020.3037136
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