Apigenin as a Natural Flavonoid Modulator of Estrogen Receptor Alpha: An Integrated Molecular Docking and Molecular Dynamics Study

Breast cancer is the most frequently diagnosed malignancy among women worldwide, with estrogen receptor alpha (ERα) representing a major therapeutic target in hormone-dependent tumors. Apigenin, a naturally occurring flavonoid found in numerous medicinal plants, has attracted considerable attention due to its reported anticancer activities. This study investigated the interaction and dynamic stability of apigenin with ERα using molecular docking and molecular dynamics (MD) simulations.

The crystal structure of the human ERα ligand-binding domain (PDB ID: 2IOK; 2.40 Å resolution) was retrieved from the Protein Data Bank. Docking protocol validation was performed by re-docking the co-crystallized ligand (IOK), yielding an RMSD value of 2.622 Å, confirming the reliability of the adopted procedure. Molecular docking revealed a favorable binding affinity for apigenin (−9.2 kcal/mol), compared with the native ligand IOK (−10.6 kcal/mol). The ligand established key hydrogen bonds with Thr347, Glu353, and Arg394, together with hydrophobic interactions involving Leu346, Ala350, Leu387, Leu391, Phe404, and Leu525.

To assess complex stability, a 100 ns MD simulation was performed. The protein backbone RMSD remained predominantly between 2.5 and 3.5 Å after equilibration, while ligand RMSD values were mainly confined to the 1.5–3.0 Å range, indicating stable retention within the binding pocket. RMSF analysis showed limited fluctuations for most binding-site residues, and persistent interactions involving Glu353, Thr347, Arg394, and Phe404 were maintained throughout the simulation. These findings suggest that apigenin forms a stable ERα complex and may serve as a promising natural lead for hormone-dependent breast cancer drug discovery.