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  • 2-Pyridone natural products as inhibitors of SARS-CoV-2 main protease #MMPMID33278462
  • Forrestall KL; Burley DE; Cash MK; Pottie IR; Darvesh S
  • Chem Biol Interact 2021[Feb]; 335 (ä): 109348 PMID33278462show ga
  • 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 (M(pro)) 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 M(pro). A search for natural, antimicrobial products with the 2-pyridone moiety was undertaken herein, and their calculated potency as inhibitors of SARS-CoV-2 M(pro) 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 M(pro). This consisted of molecular optimization of the 2-pyridone compound, docking of the compound with a crystal structure of SARS-CoV-2 M(pro), and evaluation of the predicted interactions and ligand-enzyme conformations. All compounds investigated bound to the active site of SARS-CoV-2 M(pro), close to the catalytic dyad (His-41 and Cys-145). Thirteen molecules had predicted Ki values <1 muM. 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 M(pro) and with desirable drug-like properties, which may lead to the rapid discovery of a treatment for COVID-19.
  • |Antiviral Agents/chemistry/*metabolism/pharmacokinetics[MESH]
  • |Biological Products/chemistry/*metabolism/pharmacokinetics[MESH]
  • |Caco-2 Cells[MESH]
  • |Catalytic Domain[MESH]
  • |Coronavirus 3C Proteases/chemistry/*metabolism[MESH]
  • |Cysteine Proteinase Inhibitors/chemistry/*metabolism/pharmacokinetics[MESH]
  • |Humans[MESH]
  • |Hydrogen Bonding[MESH]
  • |Molecular Docking Simulation[MESH]
  • |Molecular Structure[MESH]
  • |Protein Binding[MESH]
  • |Pyridones/chemistry/*metabolism/pharmacokinetics[MESH]
  • |SARS-CoV-2/*enzymology[MESH]

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  • suck abstract from ncbi

    109348 ä.335 2021