Quantitative structure-activity relationship for estrogenic flavonoids from Psoralea corylifolia

Area of Science:

• Pharmacology
• Computational Chemistry
• Molecular Biology

Background:

• Psoralea corylifolia flavonoids possess potential estrogenic activities.
• Estrogenic compounds interact with the human estrogen receptor alpha ligand binding domain (hERα-LBD).
• Understanding these interactions is crucial for drug discovery and development.

Purpose of the Study:

• To investigate the estrogenic activities of Psoralea corylifolia flavonoids using in vitro and in silico methods.
• To develop a fluorescence polarization (FP) assay for flavonoid binding to hERα-LBD.
• To explore the binding modes and structure-activity relationships of these flavonoids with hERα-LBD.

Main Methods:

• Production of soluble recombinant human estrogen receptor alpha ligand binding domain (hERα-LBD) in E. coli.
• Development of a fluorescence polarization (FP) assay using coumestrol (CS) as a tracer for competition binding experiments.
• Molecular modeling, including molecular docking, and quantitative structure-activity relationship (QSAR) analysis.

Main Results:

• The FP assay indicated that most tested flavonoids bind to hERα-LBD as affinity ligands, with the exception of corylin.
• Molecular docking revealed that flavonoids fit into the hydrophobic binding pocket of hERα-LBD, stabilized by hydrophobic and hydrogen-bonding interactions.
• QSAR analysis showed a strong correlation (R-squared = 0.9722) between docking scores and experimental binding affinities, confirming structure-dependent estrogenic potency.

Conclusions:

• Flavonoid binding to hERα-LBD is structure-dependent, with hydroxyl and prenyl groups being essential for estrogenic activity.
• Methylation or cyclization of these groups significantly reduces estrogenic potency.
• Molecular docking is a valuable tool for predicting receptor-binding properties of novel compounds based on their molecular structure.