Quantitative structure-activity relationship for estrogenic flavonoids from Psoralea corylifolia

A combination of in vitro and in silico approaches was employed to investigate the estrogenic activities of flavonoid compounds from Psoralea corylifolia. In order to develop fluorescence polarization (FP) assay for flavonoids, a soluble recombinant protein human estrogen receptor α ligand binding domain (hERα-LBD) was produced in Escherichia coli strain. The competition binding experiment was performed by using coumestrol (CS) as a tracer. The result of FP assay suggested that the tested flavonoids can bind to hERα-LBD as affinity ligands, except for corylin. Then, molecular modeling was conducted to explore the binding modes between hERα-LBD and flavonoids. All the tested compounds fit into the hydrophobic binding pocket of hERα-LBD. The hydrophobic and hydrogen-bonding interactions are dominant forces to stabilize the flavonoids-hERα-LBD binding. It can be speculated from molecular docking study that the hydroxyl groups and prenyl group are essential for flavonoid compounds to possess estrogenic activities. Both methylation of hydroxyl group and cyclization of prenyl group significantly diminish the estrogenic potency of flavonoids. Furthermore, quantitative structure-activity relationship (QSAR) analysis was performed by the calculated binding energies of flavonoids coupled with their determined binding affinities. Comparison between the docking scores and the pIC₅₀ values yields an R-squared value of 0.9722, indicating that the estrogenic potency of flavonoids is structure-dependent. In conclusion, molecular docking can potentially be applied for predicting the receptor-binding properties of undescribed compounds based on their molecular structure.