Exploration of Natural Anti-Hepatocellular Carcinoma Compounds Targeting XIAP-BIR3 Using Molecular Docking, Conventional, and PaCS Molecular Dynamics

Abstract

Hepatocellular carcinoma (HCC) exhibits apoptosis resistance driven in part by overexpression of X-associated inhibitor of apoptosis protein (XIAP), whose baculovirus IAP repeat domain 3 (BIR3) suppresses caspase activation. This study employed a stepwise in silico workflow to identify plant-based natural compounds targeting XIAP-BIR3. A curated library of 534 compounds from 12 medicinal plants was screened using ensemble docking (AutoDock Vina), then filtered for drug-likeness, and their poses were generated with AutoDock4. Selected candidates were evaluated through conventional molecular dynamics (MD) simulations (50 and 500 ns) and Parallel Cascade Selection MD (PaCS-MD). As a result, mangostanol and 9-hydroxycalabaxanthone showed the best affinity and stability, comparable to the co-crystal ligand 7HU as a control, while neoandrographolide showed decreased stability in the 500 ns MD simulation. PaCS-MD confirmed that 9-hydroxycalabaxanthone has a stronger initial interaction energy than neoandrographolide, but eventually fully dissociates, consistent with a dynamic and reversible interaction. Overall, mangostanol and 9-hydroxycalabaxanthone will be prioritized for in vitro/in vivo testing, underscoring the importance of a stepwise, structure-based approach.