Discovery of Diverse Natural Products as Inhibitors of SARS-CoV‑2 Mpro Protease through Virtual Screening

SARS-CoV-2 is a type of coronavirus responsible for the international outbreak of respiratory illness termed COVID-19 that forced the World Health Organization to declare a pandemic infectious disease situation of international concern at the beginning of 2020. The need for a swift response against...

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Published inJournal of chemical information and modeling Vol. 61; no. 12; pp. 6094 - 6106
Main Authors Rubio-Martínez, Jaime, Jiménez-Alesanco, Ana, Ceballos-Laita, Laura, Ortega-Alarcón, David, Vega, Sonia, Calvo, Cristina, Benítez, Cristina, Abian, Olga, Velázquez-Campoy, Adrián, Thomson, Timothy M., Granadino-Roldán, José Manuel, Gómez-Gutiérrez, Patricia, Pérez, Juan J.
Format Journal Article
LanguageEnglish
Published Washington American Chemical Society 27.12.2021
Subjects
Binding
Binding energy
Chemical compounds
Coordination compounds
Coronaviruses
COVID-19
Free energy
In vitro methods and tests
Infectious diseases
Molecular dynamics
Natural products
Pharmaceutical Modeling
Pharmacology
Protease
Protease inhibitors
Screening
Severe acute respiratory syndrome coronavirus 2
Viral diseases
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Summary:SARS-CoV-2 is a type of coronavirus responsible for the international outbreak of respiratory illness termed COVID-19 that forced the World Health Organization to declare a pandemic infectious disease situation of international concern at the beginning of 2020. The need for a swift response against COVID-19 prompted to consider different sources to identify bioactive compounds that can be used as therapeutic agents, including available drugs and natural products. Accordingly, this work reports the results of a virtual screening process aimed at identifying antiviral natural product inhibitors of the SARS-CoV-2 Mpro viral protease. For this purpose, ca. 2000 compounds of the Selleck database of Natural Compounds were the subject of an ensemble docking process targeting the Mpro protease. Molecules that showed binding to most of the protein conformations were retained for a further step that involved the computation of the binding free energy of the ligand-Mpro complex along a molecular dynamics trajectory. The compounds that showed a smooth binding free energy behavior were selected for in vitro testing. From the resulting set of compounds, five compounds exhibited an antiviral profile, and they are disclosed in the present work.
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ISSN:1549-9596
1549-960X
1549-960X
DOI:10.1021/acs.jcim.1c00951