In silico investigation of natural stilbenes from berries and grapes and their derivatives as potential ASPH inhibitors for hepatocellular carcinoma

Stilbenes are a diverse class of polyphenolic phytochemicals, including resveratrol, pinosylvin, and pterostilbene, that have attracted significant attention for their potential therapeutic applications. These compounds are synthesized by plants such as grapes, peanuts, and mulberries as protective responses to environmental stress. Aspartyl/asparaginyl β-hydroxylase (ASPH) is a transmembrane enzyme that is overexpressed in several malignancies, including hepatocellular carcinoma (HCC). As HCC is a leading cause of cancer-related mortality worldwide, ASPH plays a crucial role in tumour proliferation, migration, and metastasis, making it a promising molecular target for anticancer therapy. In this study, the inhibitory potential of stilbene derivatives against ASPH was investigated using an integrated in silico approach. Natural stilbenes and their derivatives were initially screened through molecular docking to evaluate their binding affinity toward ASPH. The pharmacokinetic and toxicity profiles of the selected compounds were further assessed using ADMET predictions, which indicated favourable drug-likeness and safety parameters. To evaluate the stability of the protein-ligand complexes, 200 ns molecular dynamics simulations were performed, among which oxyresveratrol exhibited the lowest structural fluctuations and the greatest complex stability. Solvent-accessible surface area and hydrogen-bond assessments confirmed strong interactions between the ligands and the active site of ASPH. A detailed computational investigation of stilbenes and their interactions with ASPH is still lacking in the current literature, and this study aims to address this gap. These findings suggest that stilbene derivatives are promising scaffolds for the development of ASPH-targeted anticancer agents and provide a computational basis for future experimental validation in HCC therapy.