Structural Characterization of the Binding Interactions of Various Endogenous Estrogen Metabolites with Human Estrogen Receptor α and β Subtypes: A Molecular Modeling Study

In the present study, we used the molecular docking approach to study the binding interactions of various derivatives of 17β-estradiol (E(2)) with human estrogen receptor (ER) α and β. First, we determined the suitability of the molecular docking method to correctly predict the binding modes and interactions of two representative agonists (E(2) and diethylstilbesterol) in the ligand binding domain (LBD) of human ERα. We showed that the docked structures of E(2) and diethylstilbesterol in the ERα LBD were almost exactly the same as the known crystal structures of ERα in complex with these two estrogens. Using the same docking approach, we then characterized the binding interactions of 27 structurally similar E(2) derivatives with the LBDs of human ERα and ERβ. While the binding modes of these E(2) derivatives are very similar to that of E(2), there are distinct subtle differences, and these small differences contribute importantly to their differential binding affinities for ERs. In the case of A-ring estrogen derivatives, there is a strong inverse relationship between the length of the hydrogen bonds formed with ERs and their binding affinity. We found that a better correlation between the computed binding energy values and the experimentally determined logRBA values could be achieved for various A-ring derivatives by re-adjusting the relative weights of the van der Waals interaction energy and the Coulomb interaction energy in computing the overall binding energy values.