High-Throughput Screening and Quantum Mechanics for Identifying Potent Inhibitors Against Mac1 Domain of SARS-CoV-2 Nsp3.
IEEE/ACM Trans Comput Biol Bioinform
; 18(4): 1262-1270, 2021.
Article
in English
| MEDLINE | ID: covidwho-1349900
ABSTRACT
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Coronavirus Papain-Like Proteases
/
SARS-CoV-2
/
COVID-19
/
COVID-19 Drug Treatment
Limits:
Humans
Language:
English
Journal:
ACM Trans Comput Biol Bioinform
Journal subject:
Biology
/
Medical Informatics
Year:
2021
Document Type:
Article
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