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Published on: October 11, 2013
Toward the Identification of Natural Antiviral Drug Candidates against Merkel Cell Polyomavirus: Computational Drug
Amer H Asseri1,2, Md Jahidul Alam3, Faisal Alzahrani1,4
1Biochemistry Department, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia.
Abstract:
Merkel cell carcinoma (MCC) is a rare form of aggressive skin cancer mainly caused by Merkel cell polyomavirus (MCPyV). Most MCC tumors express MCPyV large T (LT) antigens and play an important role in the growth-promoting activities of oncoproteins. Truncated LT promotes tumorigenicity as well as host cell proliferation by activating the viral replication machinery, and inhibition of this protein in humans drastically lowers cellular growth linked to the corresponding cancer. Our study was designed with the aim of identifying small molecular-like natural antiviral candidates that are able to inhibit the proliferation of malignant tumors, especially those that are aggressive, by blocking the activity of viral LT protein. To identify potential compounds against the target protein, a computational drug design including molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) approaches were applied in this study. Initially, a total of 2190 phytochemicals isolated from 104 medicinal plants were screened using the molecular docking simulation method, resulting in the identification of the top five compounds having the highest binding energy, ranging between -6.5 and -7.6 kcal/mol. The effectiveness and safety of the selected compounds were evaluated based on ADME and toxicity features. A 250 ns MD simulation confirmed the stability of the selected compounds bind to the active site (AS) of the target protein. Additionally, MM-GBSA analysis was used to determine the high values of binding free energy (ΔG bind) of the compounds binding to the target protein. The five compounds identified by computational approaches, Paulownin (CID: 3084131), Actaealactone (CID: 11537736), Epigallocatechin 3-O-cinnamate (CID: 21629801), Cirsilineol (CID: 162464), and Lycoricidine (CID: 73065), can be used in therapy as lead compounds to combat MCPyV-related cancer. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the virus.
Insights
Researchers identified five natural compounds that may inhibit Merkel cell carcinoma (MCC) by blocking the Merkel cell polyomavirus (MCPyV) large T antigen. These findings offer potential new therapies for aggressive MCC.
Area of Science:
- Computational drug discovery
- Oncology
- Virology
Background:
- Merkle cell carcinoma (MCC) is a rare, aggressive skin cancer often caused by Merkel cell polyomavirus (MCPyV).
- MCPyV large T (LT) antigens are crucial for MCC tumor growth and proliferation.
- Inhibiting MCPyV LT is a potential therapeutic strategy for MCC.
Purpose of the Study:
- To identify natural, small-molecule antiviral compounds that inhibit MCPyV LT antigen activity.
- To find novel therapeutic candidates for aggressive MCC by targeting viral oncoproteins.
Main Methods:
- Computational drug design including molecular docking, ADME/toxicity prediction, molecular dynamics (MD) simulations, and MM-GBSA analysis.
- Screening of 2190 phytochemicals against the MCPyV LT protein's active site.
- In silico evaluation of binding energy, stability, and free energy of interaction for top-ranked compounds.
Main Results:
- Five natural compounds (Paulownin, Actaealactone, Epigallocatechin 3-O-cinnamate, Cirsilineol, Lycoricidine) showed high binding affinity to MCPyV LT.
- MD simulations confirmed the stable binding of these compounds to the LT active site over 250 ns.
- MM-GBSA analysis indicated significant binding free energies for the identified phytochemicals.
Conclusions:
- The identified compounds are promising lead candidates for developing new therapies against MCPyV-related MCC.
- Further experimental validation is necessary to confirm the antiviral and anti-cancer efficacy of these compounds in vitro and in vivo.
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