Identification of amentoflavone as a potent SARS-CoV-2 Mpro inhibitor : a combination of computational studies and in vitro biological evaluation
Small-molecule inhibitors of SARS-CoV-2 Mpro that block the active site pocket of the viral main protease have been considered potential therapeutics for the development of drugs against SARS-CoV-2. Here, we report the identification of amentoflavone (a biflavonoid) through docking-based virtual screening of a library comprised of 231 compounds consisting of flavonoids and isoflavonoids. The docking results were further substantiated through extensive analysis of the data obtained from all-atom 150 ns MD simulation. End-state effective free energy calculations using MM-PBSA calculations further suggested that (Ra)-amentoflavone (C3'-C8''-atropisomer) may show a greater binding affinity towards the Mpro than (Sa)-amentoflavone. In vitro cytotoxicity assay established that amentoflavone showed a high CC50 value indicating much lower toxicity. Further, potent inhibition of the Mpro by amentoflavone was established by studying the effect on HEK293T cells treated with SARS-CoV-2 Mpro expressing plasmid.Communicated by Ramaswamy H. Sarma.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Journal of biomolecular structure & dynamics - (2024) vom: 23. Jan., Seite 1-19 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bhattacharya, Prabuddha [VerfasserIn] |
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| Themen: |
Crystal violet staining |
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| Anmerkungen: |
Date Revised 24.01.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1080/07391102.2024.2304676 |
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| 520 | |a Small-molecule inhibitors of SARS-CoV-2 Mpro that block the active site pocket of the viral main protease have been considered potential therapeutics for the development of drugs against SARS-CoV-2. Here, we report the identification of amentoflavone (a biflavonoid) through docking-based virtual screening of a library comprised of 231 compounds consisting of flavonoids and isoflavonoids. The docking results were further substantiated through extensive analysis of the data obtained from all-atom 150 ns MD simulation. End-state effective free energy calculations using MM-PBSA calculations further suggested that (Ra)-amentoflavone (C3'-C8''-atropisomer) may show a greater binding affinity towards the Mpro than (Sa)-amentoflavone. In vitro cytotoxicity assay established that amentoflavone showed a high CC50 value indicating much lower toxicity. Further, potent inhibition of the Mpro by amentoflavone was established by studying the effect on HEK293T cells treated with SARS-CoV-2 Mpro expressing plasmid.Communicated by Ramaswamy H. Sarma | ||
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