Integrated experimental and computational evaluation of atractylenolide III from Tubipora musica for anticancer lead identification

Abstract Hepatocellular carcinoma (HCC) remains a major global health challenge, with over 900,000 new cases annually and a pronounced male predominance. In pursuit of novel, low-toxicity therapeutics, this study isolated Atractylenolide III from the marine coral Tubipora musica and demonstrated measurable, dose-dependent cytotoxic activity against HepG2 liver cancer cells, achieving an IC 50 value of 15.50 µg/mL and reducing cell viability to 25.0% at 25 µg/mL. To investigate potential molecular targets and propose hypothetical mechanism pathways, we employed a multi-layered computational strategy. Molecular docking across 76 cancer-associated proteins identified a strong binding affinity (-9.6 kcal/mol) with CD1b (PDB ID: 1GZP), a T-cell surface glycoprotein key to lipid antigen presentation and tumor immunology. Short-term molecular dynamics (MD) simulations were conducted to provide a preliminary structural-viability filter for this complex under physiological conditions. Pharmacophore modeling expanded the screening to 1,513 structurally related compounds, pinpointing ZINC64701878 as a superior candidate with enhanced binding affinity (-12.7 kcal/mol). Density functional theory (DFT) calculations supported its high reactivity, and pharmacokinetic profiling suggested favorable drug-likeness. Together, these findings propose a theoretical framework for marine-derived compounds as potential leads for HCC therapy. While the cytotoxicity assay provides initial phenotypic support, the primary contribution of this study lies in establishing a predictive computational-experimental framework to guide future in vivo and mechanistic investigations.