In silico screening and molecular dynamics simulations of Epicatechin as an inhibitor of EBV LMP1.

Epstein-Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) is a critical oncoprotein and a high-value target for therapeutics against EBV-associated malignancies. This study employed an integrated in silico approach-combining virtual screening, molecular docking, 250 ns all-atom Molecular Dynamics (MD) simulations in a lipid bilayer, and ADMET prediction-to identify potent LMP1 inhibitors among nutraceutical compounds. Virtual screening of over 700 compounds led to the selection of five top ligands for MD analysis against the full-length LMP1 protein. MD simulations revealed a crucial divergence from static docking, with Epicatechin and Vitamin D2 emerging as the potential stable binders, targeting the protein's C-Terminal Activation Region (CTAR) and Transmembrane Domain (TMD). Epicatechin was predicted as the most thermodynamically favourable binder, exhibiting the strongest total binding free energy (ΔTOTAL = -29.07 ± 1.72 kcal/mol), supported by stable hydrogen bond formation with the key oncogenic residues GLU_335 and GLU_336. Comparatively, Vitamin D2 has better compact and structurally stable complex (lowest Rgyr). Crucially, ADMET analysis provided the clinical filter pending experimental confirmation. While Ginkgolide-B showed superior ADME parameters, its major liability as a strong CYP3A4 inhibitor limited its clinical viability. In contrast, Epicatechin potentially offered a favourable balance: strong binding thermodynamics paired with a superior metabolic profile (minimal CYP inhibition). These results strongly suggest that common nutraceuticals, particularly Epicatechin, provide promising, safer, and chemically tractable scaffolds for the development of multi-target small-molecule inhibitors against EBV latency proteins. This work underscores the potential of nutraceuticals in anti-EBV strategies, supporting multi-target approaches for EBV-related diseases.