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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F21%3A00544596" target="_blank" >RIV/61388963:_____/21:00544596 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1109/TCBB.2020.3037136" target="_blank" >https://doi.org/10.1109/TCBB.2020.3037136</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1109/TCBB.2020.3037136" target="_blank" >10.1109/TCBB.2020.3037136</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10609 - Biochemical research methods

Projekt

<a href="/cs/project/EF16_019%2F0000729" target="_blank" >EF16_019/0000729: Chemická biologie pro vývoj nových terapií</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

I E E E - A C M Transactions on Computational Biology and Bioinformatics

ISSN

1545-5963

e-ISSN

1557-9964

Svazek periodika

18

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

9

Strana od-do

1262-1270

Kód UT WoS článku

000682137300006

EID výsledku v databázi Scopus

2-s2.0-85097955294