Potential Pregnane X Receptor-Related Safety Liability of the Taccalonolide Scaffold: A ProTox, Molecular Docking, and Molecular Dynamics Study

Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor whose inappropriate modulation may contribute to safety liabilities. In this study, 20 taccalonolides were screened in silico to identify compounds with potential PXR-related safety relevance and stable binding propensity toward the PXR ligand-binding domain (PXR-LBD). ProTox provided an initial signal supporting a structure-based evaluation. Docking into PXR-LBD (PDB: 1M13) prioritized Taccalonolide A (1) (-10.90 kcal/mol), Taccalonolide B (2) (-11.11 kcal/mol), and Taccalonolide AG (3) (-10.99 kcal/mol) for 30-ns molecular dynamics simulations. All three complexes remained stable. Taccalonolide B (2) showed the most stable ligand pose, whereas Taccalonolide A (1) maintained the highest hydrogen-bond persistence. In contrast, Taccalonolide AG (3) displayed minimal hydrogen bonding toward the end of the simulation. Analysis of COM(LIG)-COM(POCKET) distance indicated that Taccalonolide B (2) and Taccalonolide AG (3) stabilized farther from the pocket center, suggesting occupancy of an edge or sub-pocket region within the binding site. Overall, the combined docking and molecular dynamics results support stable PXR binding for Taccalonolide A (1) and Taccalonolide B (2) through distinct interaction patterns and support further experimental validation to clarify their potential PXR-related safety liability.