Evaluation of 6-substituted coumarins as SARS-CoV-2 main protease inhibitors: enzymatic, cellular, and computational insights.
9 affiliations
- 1Biomedical Research Division, Korea Institute of Science and Technology (KIST) Seoul 02792 Republic of Korea [email protected] [email protected].
- 2Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University Mansoura 35516 Egypt.
- 3Center for Natural Product Systems Biology, KIST Gangneung Institute of Natural Products Gangneung 25451 Republic of Korea [email protected].
- 4Natural Product Applied Science, KIST School, University of Science and Technology Gangneung 25451 Republic of Korea.
- 5Zoonotic Virus Laboratory, Institut Pasteur Korea Seongnam Republic of Korea [email protected].
- 6Department of Medicinal Chemistry, Faculty of Pharmacy, King Salman International University (KSIU) South Sinai 46612 Egypt.
- 7Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Qassim University Buraydah 51452 Saudi Arabia.
- 8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University Kafrelsheikh P.O. Box 33516 Egypt [email protected].
- 9Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology Seoul 02792 Republic of Korea.
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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BibTeX
@article{eldamasy2026evaluation,
title = {{Evaluation of 6-substituted coumarins as SARS-CoV-2 main protease inhibitors: enzymatic, cellular, and computational insights.}},
author = {Ashraf K El-Damasy and Md Sofequl Islam Mukim and Sangeun Jeon and Mahmoud A El Hassab and Suliman A Almahmoud and Eun-Kyoung Bang and Wagdy M Eldehna and Dae-Geun Song and Seungtaek Kim and Gyochang Keum},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra07298d},
url = {https://europepmc.org/article/MED/42835829},
note = {CC BY},
}
RIS
TY - JOUR
TI - Evaluation of 6-substituted coumarins as SARS-CoV-2 main protease inhibitors: enzymatic, cellular, and computational insights.
AU - Ashraf K El-Damasy
AU - Md Sofequl Islam Mukim
AU - Sangeun Jeon
AU - Mahmoud A El Hassab
AU - Suliman A Almahmoud
AU - Eun-Kyoung Bang
AU - Wagdy M Eldehna
AU - Dae-Geun Song
AU - Seungtaek Kim
AU - Gyochang Keum
PY - 2026
DA - 2026/10/05
JO - RSC advances
DO - 10.1039/d6ra07298d
UR - https://europepmc.org/article/MED/42835829
AB - 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.
SN - 2046-2069
ER -