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Unraveling the mechanism of arbidol binding and inhibition of SARS-CoV-2: Insights from atomistic simulations.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2021 Mar 05; Vol. 894, pp. 173836. Date of Electronic Publication: 2020 Dec 31. - Publication Year :
- 2021
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Abstract
- The COVID-19 pandemic has spread rapidly and poses an unprecedented threat to the global economy and human health. Broad-spectrum antivirals are currently being administered to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). China's prevention and treatment guidelines suggest the use of an anti-influenza drug, arbidol, for the clinical treatment of COVID-19. Reports indicate that arbidol could neutralize SARS-CoV-2. Monotherapy with arbidol is superior to lopinavir-ritonavir or favipiravir for treating COVID-19. In SARS-CoV-2 infection, arbidol acts by interfering with viral binding to host cells. However, the detailed mechanism by which arbidol induces the inhibition of SARS-CoV-2 is not known. Here, we present atomistic insights into the mechanism underlying membrane fusion inhibition of SARS-CoV-2 by arbidol. Molecular dynamics (MD) simulation-based analyses demonstrate that arbidol binds and stabilizes at the receptor-binding domain (RBD)/ACE2 interface with a high affinity. It forms stronger intermolecular interactions with the RBD than ACE2. Analyses of the detailed decomposition of energy components and binding affinities revealed a substantial increase in the affinity between the RBD and ACE2 in the arbidol-bound RBD/ACE2 complex, suggesting that arbidol generates favorable interactions between them. Based on our MD simulation results, we propose that the binding of arbidol induces structural rigidity in the viral glycoprotein, thus restricting the conformational rearrangements associated with membrane fusion and virus entry. Furthermore, key residues of the RBD and ACE2 that interact with arbidol were identified, opening the door for developing therapeutic strategies and higher-efficacy arbidol derivatives or lead drug candidates.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Subjects :
- Angiotensin-Converting Enzyme 2 metabolism
Computer Simulation
Glycoproteins drug effects
Glycoproteins metabolism
Humans
Membrane Fusion drug effects
Models, Molecular
Molecular Conformation
Molecular Docking Simulation
Molecular Dynamics Simulation
Protein Domains
COVID-19 Drug Treatment
Antiviral Agents metabolism
Antiviral Agents pharmacology
Indoles metabolism
Indoles pharmacology
SARS-CoV-2 drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 894
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 33387467
- Full Text :
- https://doi.org/10.1016/j.ejphar.2020.173836