Abstract
Introduction: The androgen receptor (AR) is a critical therapeutic target in prostate cancer (PCa), underscoring the urgent need for novel inhibitors capable of overcoming resistance to current therapies. This study identifies the natural pentacyclic triterpenoid β-amyrin as a novel promising candidate AR antagonist through comprehensive in silico profiling.
Methods: The chemical structure of β-amyrin was used to identify ethylestrenol as a structurally similar drug via GoDrugBank (similarity threshold>0.8). The androgen receptor, identified as its target, was prepared for molecular docking. β-amyrin was docked into the AR ligand-binding site using AutoDock Vina, and the resulting interactions were analyzed using PLIP and LigPlot+. Binding stability was assessed through coarse-grained dynamics simulations using the CABSflex webserver. A ligand-based pharmacophore model was constructed from established AR inhibitors, and ADMET profiles were predicted using the ADMET.ai webserver.
Results: Molecular docking revealed high-affinity binding of β-amyrin to the AR ligand-binding domain (ΔG=-6.97 kcal/mol), involving key interactions with residues required for antagonist activity, including a stabilizing hydrogen bond with GLN711. Coarse-grained dynamics simulations confirmed the exceptional structural stability of the β-amyrin-AR complex, revealing ligand-induced structural rigidity indicative of true antagonist behavior. Pharmacophore modeling demonstrated that the stereoelectronic features of β-amyrin align precisely with those of established AR inhibitors. Furthermore, in silico ADMET profiling further supported its drug-like potential, predicting favorable oral absorption and a promising safety profile with low risks of hepatotoxicity and genotoxicity.
Conclusion: These multi-faceted computational findings provide robust evidence that β-amyrin represents a promising, naturally derived scaffold for the development of AR antagonists.