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Identification of Mulberrofuran as a potent inhibitor of hepatitis A virus 3Cpro and RdRP enzymes through structure-based virtual screening, dynamics simulation, and DFT studies

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Abstract

Hepatitis is a medical condition characterized by inflammation of the liver. It is commonly caused by the hepatitis viruses A, B, C, D, and E. Hepatitis A virus (HAV) is highly contagious and can spread from infected individuals, through contaminated food, blood, or can also be water-borne. As per the statistics of World Health Organization (WHO), HAV infects about 1.4 million individuals each year globally. In this research work, we have focused on identifying natural product-based potential inhibitors for the two major enzymes of HAV namely 3C proteinase (3Cpro) and RNA-directed RNA polymerase (RdRP). The enzyme 3Cpro plays an important role in proteolytic activity that promotes viral maturation and infectivity. RNA-directed RNA polymerase facilitate viral replication and transcription. Structure-based virtual screening was carried out using NPACT database that contains a collection of 1574 curated plant-derived natural compounds that are validated by experiments. The screening procedure identified the phytochemical Mulberrofuran W, which could bind to both the targets 3Cpro and RdRP. The phytochemical Mulberrofuran W also had better binding affinity compared to the control compounds atropine and pyridinyl ester, which are previously identified inhibitors of HAV 3Cpro and RdRP, respectively. The Mulberrofuran W bound 3Cpro and RdRP complexes were subjected to 200 ns molecular dynamics simulations and were found to be stable and interacting with the active site of the enzymes throughout the course of complex MD simulations. In addition to DFT, MMGBSA studies were also performed to validate the identified potential inhibitor further. The identified phytochemical Mulberrofuran W can be considered as a new potential drug candidate and could be taken up for experimental evaluation against HAV infection.

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Acknowledgements

The authors are grateful to the management of SASTRA Deemed University for providing all the necessary facilities. The authors thankfully acknowledge the high-performance computational facility in the School of Computing at SASTRA Deemed University for providing computational resources to complete the simulation studies. AJ is thankful to Department of Science & Technology (DST), Government of India (No. DST: SB/YS/LS/2012). MS is thankful for the funding as Senior Research Fellow grant from ICMR-SRF (No. Fellowship/96/2022-ECD-II, IRIS ID No. 2021-11346/F96).

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  1. Department of Bioinformatics, School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur, 613401, India

    Muthusamy Sureshan, Sathishkumar Brintha & Arunachalam Jothi

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MS: Data Curation, Investigation, Visualization, Validation, Writing, reviewing & editing—Original Draft. SB: Investigation, Visualization. AJ: Conceptualization, Writing—Review & Editing, Resources, Supervision, Funding acquisition.

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Sureshan, M., Brintha, S. & Jothi, A. Identification of Mulberrofuran as a potent inhibitor of hepatitis A virus 3Cpro and RdRP enzymes through structure-based virtual screening, dynamics simulation, and DFT studies. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10679-7

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