2-Pyridone natural products as inhibitors of SARS-CoV-2 main protease

The disease, COVID-19, is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) for which there is currently no treatment. The SARS-CoV-2 main protease (Mpro) is an important enzyme for viral replication. Small molecules that inhibit this protease could lead to an effective COVID-19 trea...

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Bibliographic Details
Published in:Chemico-biological interactions 2021-02, Vol.335, p.109348-109348, Article 109348
Main Authors: Forrestall, Katrina L., Burley, Darcy E., Cash, Meghan K., Pottie, Ian R., Darvesh, Sultan
Format: Article
Language:English
Subjects:
2-Pyridone
Antiviral Agents - chemistry
Antiviral Agents - metabolism
Antiviral Agents - pharmacokinetics
AutoDock
Biological Products - chemistry
Biological Products - metabolism
Biological Products - pharmacokinetics
Caco-2 Cells
Catalytic Domain
Coronavirus 3C Proteases - chemistry
Coronavirus 3C Proteases - metabolism
COVID-19
Cysteine Proteinase Inhibitors - chemistry
Cysteine Proteinase Inhibitors - metabolism
Cysteine Proteinase Inhibitors - pharmacokinetics
Humans
Hydrogen Bonding
In silico molecular modelling
Main protease (Mpro)
Molecular Docking Simulation
Molecular Structure
Protein Binding
Pyridones - chemistry
Pyridones - metabolism
Pyridones - pharmacokinetics
SARS-CoV-2 - enzymology
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
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Summary:The disease, COVID-19, is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) for which there is currently no treatment. The SARS-CoV-2 main protease (Mpro) is an important enzyme for viral replication. Small molecules that inhibit this protease could lead to an effective COVID-19 treatment. The 2-pyridone scaffold was previously identified as a possible key pharmacophore to inhibit SARS-CoV-2 Mpro. A search for natural, antimicrobial products with the 2-pyridone moiety was undertaken herein, and their calculated potency as inhibitors of SARS-CoV-2 Mpro was investigated. Thirty-three natural products containing the 2-pyridone scaffold were identified from the literature. An in silico methodology using AutoDock was employed to predict the binding energies and inhibition constants (Ki values) for each 2-pyridone-containing compound with SARS-CoV-2 Mpro. This consisted of molecular optimization of the 2-pyridone compound, docking of the compound with a crystal structure of SARS-CoV-2 Mpro, and evaluation of the predicted interactions and ligand-enzyme conformations. All compounds investigated bound to the active site of SARS-CoV-2 Mpro, close to the catalytic dyad (His-41 and Cys-145). Thirteen molecules had predicted Ki values 
ISSN:0009-2797
1872-7786
DOI:10.1016/j.cbi.2020.109348