Repurposing of drug candidates against Epstein–Barr virus: Virtual screening, docking computations, molecular dynamics, and quantum mechanical study
Mahmoud A. A. Ibrahim, Alaa M. A. Hassan, Eslam A. R. Mohamed, Gamal A. H. Mekhemer, Peter A. Sidhom, Mohamed A. El-Tayeb, Shahzeb Khan, Tamer Shoeib, Mahmoud E. S. Soliman, Alaa H. M. Abdelrahman
Abstract
Epstein–Barr virus (EBV) was the first tumor virus identified in humans, and it is mostly linked to lymphomas and cancers of epithelial cells. Nevertheless, there is no FDA-licensed drug feasible for this ubiquitous EBV viral contagion. EBNA1 (Epstein-Barr nuclear antigen 1) plays several roles in the replication and transcriptional of latent gene expression of the EBV, making it an attractive druggable target for the treatment of EBV-related malignancies. The present study targets EBV viral reactivation and upkeep by inhibiting EBNA1 utilizing a drug-repurposing strategy.
Introduction
Epstein-Barr virus (EBV), or human herpesvirus 4, is a human lymphotropic herpesvirus widely distributed and linked to several malignancies [1]. EBV establishes a latent infection in B cells in more than 95% of the adult global population, which is considered a significant risk factor [2]. In addition to infecting B lymphocytes, EBV targets epithelial cells to produce infectious mononucleosis [3]. Once the EBV virus has successfully established latent infection in a cell, it may reactivate several times in the course of an individual’s life, leading to either lytic or abortive replication [4].
Materials and method
Computational methodology
Target preparation
The 3D structure of EBNA1 in complex with KWG (PDB code: 6NPP) was downloaded in the PDB format from the RCSB website [19]. All heteroatoms, small molecules, and ions were removed for the protein preparation. After that, the H++ web server was utilized to determine the protonation states of titratable amino acids, pursued by inserting H-atoms [20].
Results and discussion
Docking assessment
To assess the employed docking protocol, re-docking of the co-crystallized KWG inhibitor was executed towards EBNA1. The docking outcomes displayed a good docking score of −7.8 kcal/mol. The calculated RMSD (root-mean-square deviation) between the native binding mode and the anticipated docking pose was found to be 0.69 Å, demonstrating the two poses almost entirely overlapped (Fig 2). These findings revealed that AutoDock4.2.6 software could accurately and successfully predict the correct binding mode of inhibitor inside the binding pocket of EBNA1. Therefore, the applied docking protocol was reliable for the virtual screening of the SuperDRUG2 database to identify potential EBNA1 inhibitors.
Acknowledgments
The authors extend their appreciation to the Researchers Supporting Project number (RSPD2024R678), King Saud University, Riyadh, Saudi Arabia. The computational work was completed with resources provided by the CompChem Lab (Minia University, Egypt, hpc.compchem.net), Center for High-Performance Computing (Cape Town, South Africa, http://www.chpc.ac.za), and Bibliotheca Alexandrina (http://hpc.bibalex.org).
Citation: Ibrahim MAA, Hassan AMA, Mohamed EAR, Mekhemer GAH, Sidhom PA, El-Tayeb MA, et al. (2024) Repurposing of drug candidates against Epstein–Barr virus: Virtual screening, docking computations, molecular dynamics, and quantum mechanical study. PLoS ONE 19(11): e0312100. https://doi.org/10.1371/journal.pone.0312100
Editor: Syed Hani Abidi, Nazarbayev University School of Medicine, PAKISTAN
Received: June 22, 2024; Accepted: October 1, 2024; Published: November 15, 2024
Copyright: © 2024 Ibrahim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data can be found within the paper and Supporting information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
