Multifaceted Elucidation of the BARD1‐Targeting Mechanism of Natural Ginsenosides Through Molecular Docking, Molecular Dynamics Simulations, DFT Calculations, and MM/PBSA Analyses

ABSTRACT Breast cancer is rapidly spreading and represents a serious threat to women's health, occurring due to the uncontrolled proliferation of cells in the breast tissue. The tumor suppressor gene BARD1 must be preserved, as it plays a key role in essential processes such as DNA repair, which is closely associated with breast cancer. In our study, the binding affinity of ginsenosides derived from Panax ginseng with the BARD1 receptor was investigated in silico. The synthetic AKT inhibitor Capivasertib, selected as the control ligand, was analyzed comparatively using computational methods. Ginsenoside Rb1 exhibited the highest binding energy (‐7.8 kcal/mol) in the docking analysis, outperforming Capivasertib (‐6.3 kcal/mol). In MD simulations, Ginsenoside Rd2 and 20‐O‐Glucoseginsenoside Rf formed highly stable complexes with the BARD1 receptor. The binding energy (‐6.6 kcal/mol) obtained for the ginsenoside Rg5 ligand, whose anticancer activity has been confirmed in in vitro studies, is also in line with our findings. In MM‐(GB/PB)SA analyses, 20‐O‐Glucoseginsenoside Rf and Ginsenoside Rd2 stood out, primarily due to van der Waals forces (‐33.03 kcal/mol for 20‐O‐Glucoseginsenoside Rf) and solvation energy (‐36.2 kcal/mol for Ginsenoside Rd2), which contributed significantly to binding stability. HOMO‐LUMO energy gap of 4.10 eV in Rd2 supports high chemical reactivity. In ADMET analyses, ginsenosides generally exhibited better pharmacokinetic profiles compared to capivasertib.