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2-Pyridone natural products as inhibitors of SARS-CoV-2 main protease.
Forrestall, Katrina L; Burley, Darcy E; Cash, Meghan K; Pottie, Ian R; Darvesh, Sultan.
  • Forrestall KL; Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
  • Burley DE; Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
  • Cash MK; Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
  • Pottie IR; Department of Chemistry and Physics, Faculty of Arts and Science, Mount Saint Vincent University, Halifax, Nova Scotia, B3M 2J6, Canada; Department of Chemistry, Faculty of Science, Saint Mary's University, Halifax, Nova Scotia, B3H 3C3, Canada.
  • Darvesh S; Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada; Department of Chemistry and Physics, Faculty of Arts and Science, Mount Saint Vincent University, Halifax, Nova Scotia, B3M 2J6, Canada; Department of Medicine (Neurology), Faculty o
Chem Biol Interact ; 335: 109348, 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-956088
ABSTRACT
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 <1 µM. Glu-166 formed a key hydrogen bond in the majority of the predicted complexes, while Met-165 had some involvement in the complex binding as a close contact to the ligand. Prominent 2-pyridone compounds were further evaluated for their ADMET properties. This work has identified 2-pyridone natural products with calculated potent inhibitory activity against SARS-CoV-2 Mpro and with desirable drug-like properties, which may lead to the rapid discovery of a treatment for COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyridones / Biological Products / Cysteine Proteinase Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Journal: Chem Biol Interact Year: 2021 Document Type: Article Affiliation country: J.cbi.2020.109348

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyridones / Biological Products / Cysteine Proteinase Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Journal: Chem Biol Interact Year: 2021 Document Type: Article Affiliation country: J.cbi.2020.109348