Estrogen Receptor Subtype Ligand Selectivity: Molecular Structural Characteristics

The action of estrogens is mediated through the estrogen receptor alpha (ERα) and the more recently discovered estrogen receptor beta (ERβ). These estrogen receptor (ER) subtypes have distinct functions and differential tissue distribution patterns. Tissue- or cell-specific estrogenic activity of receptor ligands have become targets of drug research due to the potential to affect and control physiological and disease states such as breast and endometrial carcinoma, osteoporosis, and menopause. Receptor-ligand activity can be achieved in different ways such as by selective binding or selective modulation. These, in turn, are governed by the intermolecular interactions between estrogen receptors and their ligands.
The estrogen receptor ligand binding pocket has a degree of flexibility enabling binding of endogenous and synthetically-derived steroids, as well as non-steroidal molecules. Ligand fit is dependent upon aspects of size, polarity, and specific subsitution on ring and sidechain structures. Selectivity of a ligand for the estrogen receptor subtypes can be explained on the basis of differences in ligand-binding affinity, ligand potency, or ligand efficacy. In addition, molecular characteristics can lead to selective antagonism by ligands as well as antiestrogen character. Determinants of selectivity and antagonism have been elucidated using x-ray crystallography revealing various intermolecular and steric features of importance.
The present review will examine aspects of estrogenic binding including nonselective binding, and ERα/ERβ selectivity. Various chemical classes are critically examined including endogenous compounds, phytoestrogens, and other classes of interest to drug discovery and pharmaceutical product development.