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Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO.
Jiménez-Avalos, Gabriel; Vargas-Ruiz, A Paula; Delgado-Pease, Nicolás E; Olivos-Ramirez, Gustavo E; Sheen, Patricia; Fernández-Díaz, Manolo; Quiliano, Miguel; Zimic, Mirko.
  • Jiménez-Avalos G; Laboratorio de Bioinformática, Biología Molecular y Desarrollos Tecnológicos, Facultad de Ciencias y Filosofía, Departamento de Ciencias Celulares y Moleculares, Universidad Peruana Cayetano Heredia (UPCH), 15102, Lima, Peru. gabriel.jimenez.a@upch.pe.
  • Vargas-Ruiz AP; Laboratorio de Bioinformática, Biología Molecular y Desarrollos Tecnológicos, Facultad de Ciencias y Filosofía, Departamento de Ciencias Celulares y Moleculares, Universidad Peruana Cayetano Heredia (UPCH), 15102, Lima, Peru.
  • Delgado-Pease NE; Laboratorio de Bioinformática, Biología Molecular y Desarrollos Tecnológicos, Facultad de Ciencias y Filosofía, Departamento de Ciencias Celulares y Moleculares, Universidad Peruana Cayetano Heredia (UPCH), 15102, Lima, Peru.
  • Olivos-Ramirez GE; Laboratorio de Bioinformática, Biología Molecular y Desarrollos Tecnológicos, Facultad de Ciencias y Filosofía, Departamento de Ciencias Celulares y Moleculares, Universidad Peruana Cayetano Heredia (UPCH), 15102, Lima, Peru.
  • Sheen P; Laboratorio de Bioinformática, Biología Molecular y Desarrollos Tecnológicos, Facultad de Ciencias y Filosofía, Departamento de Ciencias Celulares y Moleculares, Universidad Peruana Cayetano Heredia (UPCH), 15102, Lima, Peru.
  • Fernández-Díaz M; Farmacológicos Veterinarios - FARVET S.A.C. Chincha, Lima, Peru.
  • Quiliano M; Faculty of Health Sciences, Centre for Research and Innovation, Universidad Peruana de Ciencias Aplicadas (UPC), 15023, Lima, Peru.
  • Zimic M; Laboratorio de Bioinformática, Biología Molecular y Desarrollos Tecnológicos, Facultad de Ciencias y Filosofía, Departamento de Ciencias Celulares y Moleculares, Universidad Peruana Cayetano Heredia (UPCH), 15102, Lima, Peru. mirko.zimic@upch.pe.
Sci Rep ; 11(1): 15452, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1387487
ABSTRACT
SARS-CoV-2 main protease is a common target for inhibition assays due to its high conservation among coronaviruses. Since flavonoids show antiviral activity, several in silico works have proposed them as potential SARS-CoV-2 main protease inhibitors. Nonetheless, there is reason to doubt certain results given the lack of consideration for flavonoid promiscuity or main protease plasticity, usage of short library sizes, absence of control molecules and/or the limitation of the methodology to a single target site. Here, we report a virtual screening study where dorsilurin E, euchrenone a11, sanggenol O and CHEMBL2171598 are proposed to inhibit main protease through different pathways. Remarkably, novel structural mechanisms were observed after sanggenol O and CHEMBL2171598 bound to experimentally proven allosteric sites. The former drastically affected the active site, while the latter triggered a hinge movement which has been previously reported for an inactive SARS-CoV main protease mutant. The use of a curated database of 4.8 k flavonoids, combining two well-known docking software (AutoDock Vina and AutoDock4.2), molecular dynamics and MMPBSA, guaranteed an adequate analysis and robust interpretation. These criteria can be considered for future screening campaigns against SARS-CoV-2 main protease.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Flavonoids / Coronavirus 3C Proteases / COVID-19 Limits: Humans Language: English Journal: Sci Rep Year: 2021 Document Type: Article Affiliation country: S41598-021-94951-6

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Flavonoids / Coronavirus 3C Proteases / COVID-19 Limits: Humans Language: English Journal: Sci Rep Year: 2021 Document Type: Article Affiliation country: S41598-021-94951-6