Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening.

Abstract

The global health emergency generated by coronavirus disease 2019 (COVID-19) has prompted the search for preventive and therapeutic treatments for its pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are many potential targets for drug discovery and development to tackle this disease. One of these targets is the main protease, Mpro or 3CLpro, which is highly conserved among coronaviruses. 3CLpro is an essential player in the viral replication cycle, processing the large viral polyproteins and rendering the individual proteins functional. We report a biophysical characterization of the structural stability and the catalytic activity of 3CLpro from SARS-CoV-2, from which a suitable experimental in vitro molecular screening procedure has been designed. By screening of a small chemical library consisting of about 150 compounds, the natural product quercetin was identified as reasonably potent inhibitor of SARS-CoV-2 3CLpro (Ki ~ 7 μM). Quercetin could be shown to interact with 3CLpro using biophysical techniques and bind to the active site in molecular simulations. Quercetin, with well-known pharmacokinetic and ADMET properties, can be considered as a good candidate for further optimization and development, or repositioned for COVID-19 therapeutic treatment.

• Authors: Olga Abian, David Ortega-Alarcon, Ana Jimenez-Alesanco, Laura Ceballos-Laita, Sonia Vega, Hugh T Reyburn, Bruno Rizzuti, Adrian Velazquez-Campoy
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 164 Pg. 1693-1703 (Dec 01 2020) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 32745548 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• Protease Inhibitors
• Viral Nonstructural Proteins
• Quercetin
• Cysteine Endopeptidases
• Coronavirus 3C Proteases

Topics

• Antiviral Agents (chemistry, pharmacology)
• Betacoronavirus (chemistry, drug effects, enzymology)
• COVID-19
• Catalytic Domain (drug effects)
• Coronavirus 3C Proteases
• Coronavirus Infections (drug therapy, virology)
• Cysteine Endopeptidases (chemistry, metabolism)
• Drug Discovery
• Humans
• Molecular Docking Simulation
• Pandemics
• Pneumonia, Viral (drug therapy, virology)
• Protease Inhibitors (chemistry, pharmacology)
• Protein Conformation (drug effects)
• Protein Unfolding
• Quercetin (chemistry, pharmacology)
• SARS-CoV-2
• Viral Nonstructural Proteins (antagonists & inhibitors, chemistry, metabolism)
• COVID-19 Drug Treatment