Silico study identifies the phytochemical Punicalagin as a potential inhibitor of Mpox virus that targets the envelope protein E8

Mpox News: In the ongoing battle against infectious diseases, the Mpox virus (MPXV), a relative of the smallpox virus, has emerged as a significant global health concern. Despite the availability of vaccines, there remains a pressing need for effective therapeutics, particularly as the virus continues to spread to new regions. A recent computational study conducted by researchers from Sikkim University, Sikkim Manipal University, and Vellore Institute of Technology in India has brought new hope in this regard. This Mpox News report delves into their findings, which identify two promising compounds - Maraviroc, a commercial drug used for the treatment of HIV, and Punicalagin, a natural phytochemical compound derived from pomegranates and other plants - as potential inhibitors of the MPXV, specifically targeting the envelope protein E8.


Silico study identifies the phytochemical Punicalagin as a potential inhibitor of Mpox virus that targets the envelope protein E8

Understanding the Mpox Virus and Its E8 Protein
The mpox virus, classified under the Orthopoxvirus genus, was first discovered in laboratory monkeys in 1958. Human cases were documented as early as 1970. MPXV shares significant genetic similarities with the smallpox virus, particularly in its method of infecting host cells. This similarity has made the development of treatments for mpox a priority, especially considering the virus's rapid spread in recent years, which has led to over 89,000 cases reported globally.
 
One of the critical proteins in MPXV's life cycle is the envelope protein E8. This protein plays a vital role in the virus's ability to attach to and invade host cells, making it a prime target for therapeutic intervention. The E8 protein's structure and function closely resemble that of the D8 protein in the vaccinia virus, which is known to bind to glycosaminoglycans (GAGs) on the host cell surface, facilitating viral entry.
 
The Study: Computational Investigation of Potential Inhibitors
Given the urgency of finding effective treatments for mpox, the researchers employed advanced computational techniques, including molecular docking and molecular dynamics simulations, to screen potential inhibitors of the E8 protein. This approach allows for the rapid identification of compounds that could interfere with the virus's ability to infect host cells.
In their study, the team focused on two types of compounds: commercially available drugs and natural plant-derived compounds. Among the commercial drugs, Maraviroc, an HIV entry inhibitor, stood out due to its ability to bind with the E8 protein. On the other hand, Punicalagin, a compound extracted from pomegranate peel, demonstrated even stronger binding affinity and stability in simulations.
 
Key Findings: Maraviroc and Punicalagin as Potential Inhibitors
The study's key findings are centered on the binding efficiency and stability of the Maraviroc and Punicalagin compounds when interacting with the E8 p rotein. In terms of binding affinity, Punicalagin emerged as the more potent inhibitor, with a binding energy of -9.1 kcal/mol, compared to Maraviroc's -7.8 kcal/mol. This difference suggests that Punicalagin forms a more stable and stronger interaction with the E8 protein, potentially making it a more effective therapeutic agent.
 
To validate these findings, the researchers conducted 100-nanosecond molecular dynamics simulations, which further supported Punicalagin's superior stability. The simulations revealed that the E8-Punicalagin complex exhibited lower root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) values compared to the E8-Maraviroc complex. These metrics indicate that Punicalagin maintains a more stable conformation when bound to the E8 protein, reducing the likelihood of the virus successfully attaching to and entering host cells.
 
The Role of Hydrogen Bonding and Solvent Accessibility
Another critical aspect of the study was the analysis of hydrogen bonding interactions and solvent accessibility in the E8-protein complexes. Hydrogen bonds are crucial for maintaining the stability of protein-ligand interactions. The E8-Punicalagin complex formed a higher number of hydrogen bonds compared to the E8-Maraviroc complex, further contributing to its stability.
 
Moreover, the study assessed the solvent-accessible surface area (SASA) of the protein-ligand complexes, which provides insights into how tightly a ligand binds to its target. A lower SASA value indicates that the ligand is more deeply embedded in the protein, reducing its exposure to the surrounding solvent. The E8-Punicalagin complex exhibited a lower SASA value, suggesting that Punicalagin forms a more compact and stable interaction with the E8 protein.
 
Potential for Future Therapeutics
The findings from this study are promising, suggesting that Punicalagin could be developed into a potent therapeutic agent against mpox. Its natural origin, combined with its strong binding affinity and stability, makes it an attractive candidate for further research and development. Maraviroc, while not as potent as Punicalagin, still shows potential, particularly given its existing approval for other viral infections.
 
However, it is important to note that these findings are based on computational simulations. While these methods are powerful tools for predicting the behavior of molecules, experimental validation is crucial to confirm the efficacy and safety of these compounds in real-world scenarios. The next steps will involve laboratory-based studies to test these compounds in vitro (in the lab) and in vivo (in living organisms) followed by observational clinical trials and ultimately large cohort randomized clinical trials. Fortunately, Punicalagin is a natural compudn already found in many fruits and plants and has an excellent safety profile.
 
Conclusion
In conclusion, the study conducted by the Indian research team highlights the potential of Punicalagin and Maraviroc as inhibitors of the mpox virus, specifically targeting the E8 envelope protein. Punicalagin, in particular, shows promise due to its strong binding affinity, stability, and natural origin. These findings represent a significant step forward in the search for effective treatments against mpox, a disease that has seen a resurgence in recent years. As the world continues to grapple with emerging infectious diseases, studies like this underscore the importance of innovative approaches in drug discovery.
 
The study findings were published in the peer-reviewed journal Scientific Reports.
https://www.nature.com/articles/s41598-024-70433-3
 
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