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Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main
Balasubramanian Moovarkumudalvan1, Anupriya Madhukumar Geethakumari2, Ramya Ramadoss3
1Division of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha P.O. Box 34110, Qatar.
Abstract:
The recent global health emergency caused by the coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll, both in terms of lives and economies. Vaccines against the disease have been developed, but the efficiency of vaccination campaigns worldwide has been variable due to challenges regarding production, logistics, distribution and vaccine hesitancy. Furthermore, vaccines are less effective against new variants of the SARS-CoV-2 virus and vaccination-induced immunity fades over time. These challenges and the vaccines' ineffectiveness for the infected population necessitate improved treatment options, including the inhibition of the SARS-CoV-2 main protease (Mpro). Drug repurposing to achieve inhibition could provide an immediate solution for disease management. Here, we used structure-based virtual screening (SBVS) to identify natural products (from NP-lib) and FDA-approved drugs (from e-Drug3D-lib and Drugs-lib) which bind to the Mpro active site with high-affinity and therefore could be designated as potential inhibitors. We prioritized nine candidate inhibitors (e-Drug3D-lib: Ciclesonide, Losartan and Telmisartan; Drugs-lib: Flezelastine, Hesperidin and Niceverine; NP-lib: three natural products) and predicted their half maximum inhibitory concentration using DeepPurpose, a deep learning tool for drug-target interactions. Finally, we experimentally validated Losartan and two of the natural products as in vitro Mpro inhibitors, using a bioluminescence resonance energy transfer (BRET)-based Mpro sensor. Our study suggests that existing drugs and natural products could be explored for the treatment of COVID-19.
Insights
Repurposing existing drugs and natural products shows promise for treating COVID-19. Researchers identified and validated compounds that inhibit the SARS-CoV-2 main protease (Mpro), offering potential new therapeutic options.
Area of Science:
- Virology
- Drug Discovery
- Computational Chemistry
Background:
- COVID-19 pandemic poses significant global health and economic challenges.
- Vaccine efficacy is limited by production issues, hesitancy, waning immunity, and emerging SARS-CoV-2 variants.
- Effective treatments are crucial, particularly targeting the SARS-CoV-2 main protease (Mpro).
Purpose of the Study:
- To identify potential COVID-19 treatments through drug repurposing.
- To discover natural products and FDA-approved drugs that inhibit the SARS-CoV-2 Mpro.
- To validate identified inhibitors experimentally.
Main Methods:
- Structure-based virtual screening (SBVS) of natural product and drug libraries.
- In silico prediction of half maximum inhibitory concentration (IC50) using DeepPurpose.
- Experimental validation using a bioluminescence resonance energy transfer (BRET)-based Mpro sensor.
Main Results:
- Nine candidate Mpro inhibitors were identified, including FDA-approved drugs (Ciclesonide, Losartan, Telmisartan, Flezelastine, Hesperidin, Niceverine) and three natural products.
- Losartan and two natural products were experimentally confirmed as in vitro Mpro inhibitors.
- DeepPurpose accurately predicted drug-target interactions for potential inhibitors.
Conclusions:
- Existing drugs and natural products can be repurposed to inhibit SARS-CoV-2 Mpro.
- This study provides a foundation for developing novel COVID-19 therapeutics.
- Further exploration of these compounds could lead to effective treatments for COVID-19.
