Elucidation of Agonist and Antagonist Dynamic Binding Patterns in ER-α by Integration of Molecular Docking, Molecular Dynamics Simulations and Quantum Mechanical Calculations

Estrogen receptor alpha (ER alpha) is a ligand-dependent transcriptional factor in the nuclear receptor superfamily. Many structures of ER alpha bound with agonists and antagonists have been determined. However, the dynamic binding patterns of agonists and antagonists in the binding site of ER alpha remains unclear. Therefore, we performed molecular docking, molecular dynamics (MD) simulations, and quantum mechanical calculations to elucidate agonist and antagonist dynamic binding patterns in ER alpha. 17 beta-estradiol (E2) and 4-hydroxytamoxifen (OHT) were docked in the ligand binding pockets of the agonist and antagonist bound ER alpha. The best complex conformations from molecular docking were subjected to 100 nanosecond MD simulations. Hierarchical clustering was conducted to group the structures in the trajectory from MD simulations. The representative structure from each cluster was selected to calculate the binding interaction energy value for elucidation of the dynamic binding patterns of agonists and antagonists in the binding site of ER alpha. The binding interaction energy analysis revealed that OHT binds ER alpha more tightly in the antagonist conformer, while E2 prefers the agonist conformer. The results may help identify ER alpha antagonists as drug candidates and facilitate risk assessment of chemicals through ER-mediated responses.

Automated summary

ERalpha is a ligand-dependent transcriptional factor, and this study used molecular docking, molecular dynamics simulations, and quantum mechanical calculations to elucidate the dynamic binding patterns of agonists and antagonists in ER alpha. The results showed that OHT binds ER alpha more tightly in the antagonist conformer, while E2 prefers the agonist conformer, which may have implications for drug development and risk assessment related to ER-mediated responses.