Nature of the ligand-binding pocket of estrogen receptor α and β:: The search for subtype-selective ligands and implications for the prediction of estrogenic activity

The ligand-binding pockets of estrogen receptor alpha and beta (ERalpha and ERbeta) appear to have subpockets of different size and flexibility. To find ligands that will discriminate between the two ER subtypes on the basis of affinity or efficacy, we have prepared compounds of varying size, shape, and structure. We have evaluated the binding affinity of these compounds and their potency and efficacy as transcriptional activators through ERalpha and ERbeta. In this manner, we have identified a number of ligands that show pronounced ER subtype selectivity. These studies also highlight the eclectic structure-activity relationships of estrogens and the challenges inherent in developing computational methods for the prediction of estrogenic activity.