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Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening.
Int J Biol Macromol. 2020 Dec 01; 164:1693-1703.IJ

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+Show Affiliations

Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain; Instituto de Investigación Sanitaria de Aragón (IIS Aragon), 50009 Zaragoza, Spain; Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain; Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50009 Zaragoza, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain. Electronic address: oabifra@unizar.es.Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50009 Zaragoza, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain.Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50009 Zaragoza, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain.Instituto de Investigación Sanitaria de Aragón (IIS Aragon), 50009 Zaragoza, Spain; Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50009 Zaragoza, Spain.Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50009 Zaragoza, Spain.Department of Immunology and Oncology, National Centre for Biotechnology (CNB), CSIC, 28049 Madrid, Spain.CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, 87036 Rende, Italy.Instituto de Investigación Sanitaria de Aragón (IIS Aragon), 50009 Zaragoza, Spain; Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain; Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50009 Zaragoza, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain; Fundación ARAID, Gobierno de Aragón, 50018 Zaragoza, Spain. Electronic address: adrianvc@unizar.es.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32745548

Citation

Abian, Olga, et al. "Structural Stability of SARS-CoV-2 3CLpro and Identification of Quercetin as an Inhibitor By Experimental Screening." International Journal of Biological Macromolecules, vol. 164, 2020, pp. 1693-1703.
Abian O, Ortega-Alarcon D, Jimenez-Alesanco A, et al. Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening. Int J Biol Macromol. 2020;164:1693-1703.
Abian, O., Ortega-Alarcon, D., Jimenez-Alesanco, A., Ceballos-Laita, L., Vega, S., Reyburn, H. T., Rizzuti, B., & Velazquez-Campoy, A. (2020). Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening. International Journal of Biological Macromolecules, 164, 1693-1703. https://doi.org/10.1016/j.ijbiomac.2020.07.235
Abian O, et al. Structural Stability of SARS-CoV-2 3CLpro and Identification of Quercetin as an Inhibitor By Experimental Screening. Int J Biol Macromol. 2020 Dec 1;164:1693-1703. PubMed PMID: 32745548.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening. AU - Abian,Olga, AU - Ortega-Alarcon,David, AU - Jimenez-Alesanco,Ana, AU - Ceballos-Laita,Laura, AU - Vega,Sonia, AU - Reyburn,Hugh T, AU - Rizzuti,Bruno, AU - Velazquez-Campoy,Adrian, Y1 - 2020/08/01/ PY - 2020/06/17/received PY - 2020/07/17/revised PY - 2020/07/22/accepted PY - 2020/8/4/pubmed PY - 2020/11/24/medline PY - 2020/8/4/entrez KW - Drug discovery KW - SARS-CoV-2 3CL protease KW - Structural stability SP - 1693 EP - 1703 JF - International journal of biological macromolecules JO - Int J Biol Macromol VL - 164 N2 - 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. SN - 1879-0003 UR - https://www.unboundmedicine.com/medline/citation/32745548/Structural_stability_of_SARS_CoV_2_3CLpro_and_identification_of_quercetin_as_an_inhibitor_by_experimental_screening_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0141-8130(20)33997-0 DB - PRIME DP - Unbound Medicine ER -