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Screening of Potent Phytochemical Inhibitors Against SARS-CoV-2 Main Protease: An Integrative Computational Approach
Shafi Mahmud1, Md Robiul Hasan2, Suvro Biswas2
1Department of Genetic Engineering and Biotechnology, Microbiology Laboratory, University of Rajshahi, Rajshahi, Bangladesh.
Insights
This study identifies three natural compounds—medicagol, faradiol, and flavanthrin—that effectively inhibit the SARS-CoV-2 main protease, a key target for COVID-19 drug development. Computational analysis confirms their stability and lack of toxicity, paving the way for new antiviral therapies.
Area of Science:
- Computational drug discovery
- Virology
- Medicinal chemistry
Background:
- Coronavirus disease 2019 (COVID-19) poses a significant global health and economic threat.
- The SARS-CoV-2 main protease (Mpro) is crucial for viral replication and a promising therapeutic target.
- Developing effective antiviral drugs is essential to combat the pandemic.
Purpose of the Study:
- To identify phytochemicals capable of inhibiting the SARS-CoV-2 main protease (Mpro).
- To evaluate the binding affinity and stability of potential drug candidates using computational methods.
- To assess the safety profile of identified compounds through ADMET analysis.
Main Methods:
- Construction of a phytochemical dataset from literature review.
- Molecular docking simulations to predict binding interactions with Mpro.
- Molecular dynamics simulations to assess complex stability.
- Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis.
Main Results:
- Medicagol, faradiol, and flavanthrin showed high binding affinity to the Mpro active site (-8.3 to -8.8 kcal/mol).
- Molecular dynamics simulations confirmed the stable interaction of these compounds with Mpro.
- ADMET analysis indicated no significant toxicity or carcinogenicity for the top compounds.
Conclusions:
- Medicagol, faradiol, and flavanthrin are promising candidates for developing novel SARS-CoV-2 Mpro inhibitors.
- Computational approaches are valuable for accelerating the discovery of antiviral agents.
- These findings support the development of new drugs targeting Mpro to combat COVID-19.
Abstract:
Coronavirus disease 2019 (COVID-19) is a potentially lethal and devastating disease that has quickly become a public health threat worldwide. Due to its high transmission rate, many countries were forced to implement lockdown protocols, wreaking havoc on the global economy and the medical crisis. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus for COVID-19, represent an effective target for the development of a new drug/vaccine because it is well-conserved and plays a vital role in viral replication. Mpro inhibition can stop the replication, transcription as well as recombination of SARS-CoV-2 after the infection and thus can halt the formation of virus particles, making Mpro a viable therapeutic target. Here, we constructed a phytochemical dataset based on a rigorous literature review and explored the probability that various phytochemicals will bind with the main protease using a molecular docking approach. The top three hit compounds, medicagol, faradiol, and flavanthrin, had binding scores of -8.3, -8.6, and -8.8 kcal/mol, respectively, in the docking analysis. These three compounds bind to the active groove, consisting of His41, Cys45, Met165, Met49, Gln189, Thr24, and Thr190, resulting in main protease inhibition. Moreover, the multiple descriptors from the molecular dynamics simulation, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond analysis, confirmed the stable nature of the docked complexes. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis confirmed a lack of toxicity or carcinogenicity for the screened compounds. Our computational analysis may contribute toward the design of an effective drug against the main protease of SARS-CoV-2.
