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Repurposing of FDA-approved drugs against active site and potential allosteric drug-binding sites of COVID-19 main protease.
- Source :
-
Proteins [Proteins] 2021 Nov; Vol. 89 (11), pp. 1425-1441. Date of Electronic Publication: 2021 Jul 05. - Publication Year :
- 2021
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Abstract
- The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (M <superscript>pro</superscript> ), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on M <superscript>pro</superscript> that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of M <superscript>pro</superscript> are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆G <subscript>bind</subscript> ) values. ∆G <subscript>bind</subscript> values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and - 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as M <superscript>pro</superscript> inhibitor candidates to be evaluated against SARS-CoV-2 infections.<br /> (© 2021 Wiley Periodicals LLC.)
- Subjects :
- Allosteric Site
Antiviral Agents chemistry
Antiviral Agents pharmacology
Benzofurans metabolism
Benzofurans pharmacology
Binding Sites
Bromocriptine chemistry
Bromocriptine metabolism
Bromocriptine pharmacology
Coronavirus 3C Proteases antagonists & inhibitors
Coronavirus 3C Proteases chemistry
Diosmin chemistry
Diosmin metabolism
Hydrazines chemistry
Hydrazines metabolism
Hydrazines pharmacology
Imidazoles metabolism
Imidazoles pharmacology
Ivermectin chemistry
Ivermectin metabolism
Ivermectin pharmacology
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Triazoles chemistry
Triazoles metabolism
Triazoles pharmacology
United States
United States Food and Drug Administration
Antiviral Agents metabolism
Benzofurans chemistry
Coronavirus 3C Proteases metabolism
Drug Repositioning methods
Imidazoles chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0134
- Volume :
- 89
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Proteins
- Publication Type :
- Academic Journal
- Accession number :
- 34169568
- Full Text :
- https://doi.org/10.1002/prot.26164