Structure‐Based Virtual Screening and Molecular Dynamics Identify Resorcinol as a Potential EBNA‐1 Inhibitor Against Epstein–Barr Virus

ABSTRACT The Epstein–Barr virus (EBV), a ubiquitous herpesvirus, plays a critical role in the etiology of various cancers and lymphoproliferative disorders. Currently, no effective antiviral therapy exists for EBV. This study explores the therapeutic potential of phytochemicals by targeting the EBNA‐1 protein, which is essential for viral replication and persistence in host cells. Using molecular docking and ADMET screening, we evaluated a library of 9150 phytochemicals for binding affinities against EBNA‐1, with Cidofovir (CID₆0613) as the control ligand. Our findings revealed six phytochemicals with lower docking scores than Cidofovir: Folic acid, Resorcinol, Kaempferol 3‐neohesperidoside, Grossamide, Hydroquinone, and Tetracosanoic acid. Among these, Resorcinol and Hydroquinone exhibited the most favorable ADME/toxicity profiles. These two compounds and the control interacted with the shared amino acid residues of the protein at SER516, THR585, THR590, ASN592, LEU517, MET584, PRO589, CYS591, and LEU575, indicating they bind to the same active site. The negative binding free energy of Resorcinol, Hydroquinone, and control were −25. 61, −19. 1, and −18. 21 kcal/mol, respectively. In MD simulation, Resorcinol and apo protein complex showed the highest stability, followed by Hydroquinone. Hence, we propose Resorcinol, found in Mangifera indica exudate, as the top therapeutic candidate, with Hydroquinone following closely.