Computational Investigation of Withaferin A as a Potential Inhibitor of Epstein–Barr Virus Nuclear Antigen 1 (EBNA1): Molecular Docking and ADMET Analysis

Abstract

Background: Epstein–Barr virus (EBV) is an oncogenic herpesvirus associated with several human cancers. Epstein–Barr nuclear antigen 1 (EBNA1), essential for viral latency and episome maintenance, represents a promising therapeutic target. Aim: To evaluate the binding affinity and predicted pharmacokinetic properties of Withaferin A, a natural steroidal lactone from Withania somnifera, against EBV EBNA1 using molecular docking and ADMET analysis. Methods: Withaferin A was docked against EBNA1 (PDB ID: 6NPP) using SwissDock and compared with the reference ligand KWG. Protein–ligand interactions were analyzed using BIOVIA Discovery Studio and PyMOL, while ADMET-AI was used to predict pharmacokinetic and toxicity properties. Results: Withaferin A showed stronger predicted binding affinity toward EBNA1 than the reference ligand KWG, with a minimum binding energy of −6.866 kcal/mol and an average docking score of −5.193 ± 0.727 kcal/mol, compared with −5.494 kcal/mol and −4.465 ± 0.435 kcal/mol for KWG, respectively. Withaferin A formed multiple hydrophobic interactions with key EBNA1 residues, including Phe508, Tyr510, Leu539, Pro540, Met563, Thr596, Cys598, Phe600, and Val604. ADMET analysis indicated favorable drug-likeness, intestinal absorption, oral bioavailability, and safety. Despite moderate CYP3A4 and P-glycoprotein inhibition, Withaferin A showed lower predicted risks of liver injury (0.32 vs 0.97) and carcinogenicity (0.03 vs 0.38) than the reference ligand. Conclusion: Withaferin A demonstrates promising computational activity against EBNA1, with favorable binding and ADMET properties, suggesting its potential as a lead compound for EBV-associated cancer therapy. Further molecular dynamics, in vitro, and in vivo studies are required for validation.