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Published on: May 9, 2025
Evaluation of 6-substituted coumarins as SARS-CoV-2 main protease inhibitors: enzymatic, cellular, and computational
Ashraf K El-Damasy1,2, Md Sofequl Islam Mukim3,4, Sangeun Jeon5
1Biomedical Research Division, Korea Institute of Science and Technology (KIST) Seoul 02792 Republic of Korea ph_karem2000@mans.edu.eg gkeum@kist.re.kr.
Abstract:
The SARS-CoV-2 main protease (Mpro) plays a crucial role in viral replication, making it an attractive target for antiviral drug development. This study evaluates the inhibitory potential of nineteen 6-substituted coumarin derivatives (1a-p and 2a-c) against Mpro using a FRET-based enzymatic assay. Among them, the chlorinated derivative 1f (AKE-9306) exhibited the highest potency with an IC50 value of 61.77 µM. Enzyme kinetics analysis through Michaelis-Menten and Lineweaver-Burk plots revealed that compound 1f may act through a mixed-type inhibition mechanism with a preference for the free enzyme. In cellular assays, 1f showed significant antiviral efficacy (IC50 = 16.02 µM, CC50 >50 µM, selectivity index >3.12). Molecular docking and dynamics simulations confirmed its stable interaction within the Mpro active site, supported by MM-PBSA calculations. These findings identify compound 1f as a hit coumarin-based scaffold for further optimization toward improved SARS-CoV-2 Mpro inhibition and antiviral activity.
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