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Flavonoids in Ampelopsis grossedentata as covalent inhibitors of SARS-CoV-2 3CL pro : Inhibition potentials, covalent binding sites and inhibitory mechanisms.
- Source :
-
International journal of biological macromolecules [Int J Biol Macromol] 2021 Sep 30; Vol. 187, pp. 976-987. Date of Electronic Publication: 2021 Jul 30. - Publication Year :
- 2021
-
Abstract
- Coronavirus 3C-like protease (3CL <superscript>pro</superscript> ) is a crucial target for treating coronavirus diseases including COVID-19. Our preliminary screening showed that Ampelopsis grossedentata extract (AGE) displayed potent SARS-CoV-2-3CL <superscript>pro</superscript> inhibitory activity, but the key constituents with SARS-CoV-2-3CL <superscript>pro</superscript> inhibitory effect and their mechanisms were unrevealed. Herein, a practical strategy via integrating bioactivity-guided fractionation and purification, mass spectrometry-based peptide profiling and time-dependent biochemical assay, was applied to identify the crucial constituents in AGE and to uncover their inhibitory mechanisms. The results demonstrated that the flavonoid-rich fractions (10-17.5 min) displayed strong SARS-CoV-2-3CL <superscript>pro</superscript> inhibitory activities, while the constituents in these fractions were isolated and their SARS-CoV-2-3CL <superscript>pro</superscript> inhibitory activities were investigated. Among all isolated flavonoids, dihydromyricetin, isodihydromyricetin and myricetin strongly inhibited SARS-CoV-2 3CL <superscript>pro</superscript> in a time-dependent manner. Further investigations demonstrated that myricetin could covalently bind on SARS-CoV-2 3CL <superscript>pro</superscript> at Cys300 and Cys44, while dihydromyricetin and isodihydromyricetin covalently bound at Cys300. Covalent docking coupling with molecular dynamics simulations showed the detailed interactions between the orthoquinone form of myricetin and two covalent binding sites (surrounding Cys300 and Cys44) of SARS-CoV-2 3CL <superscript>pro</superscript> . Collectively, the flavonoids in AGE strongly and time-dependently inhibit SARS-CoV-2 3CL <superscript>pro</superscript> , while the newly identified SARS-CoV-2 3CL <superscript>pro</superscript> inhibitors in AGE offer promising lead compounds for developing novel antiviral agents.<br /> (Copyright © 2021. Published by Elsevier B.V.)
- Subjects :
- Antiviral Agents chemistry
Binding Sites drug effects
Cysteine metabolism
Flavonoids chemistry
Flavonols chemistry
Flavonols pharmacology
Mass Spectrometry
Models, Molecular
Molecular Docking Simulation
Molecular Dynamics Simulation
Plant Extracts chemistry
Plant Extracts pharmacology
Protease Inhibitors chemistry
Protease Inhibitors pharmacology
Protein Binding drug effects
Protein Conformation drug effects
SARS-CoV-2 drug effects
3C Viral Proteases chemistry
3C Viral Proteases metabolism
Ampelopsis chemistry
Antiviral Agents pharmacology
Flavonoids pharmacology
SARS-CoV-2 enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0003
- Volume :
- 187
- Database :
- MEDLINE
- Journal :
- International journal of biological macromolecules
- Publication Type :
- Academic Journal
- Accession number :
- 34333006
- Full Text :
- https://doi.org/10.1016/j.ijbiomac.2021.07.167