Quantitative Structure-Activity Relationship of Various Endogenous Estrogen Metabolites for Human Estrogen Receptor α and β Subtypes: Insights into the Structural Determinants Favoring a Differential Subtype Binding

TLDR

The study aimed to identify endogenous estrogens with preferential binding to ERα or ERβ and to elucidate structural determinants of subtype selectivity by measuring binding affinities of 74 natural or synthetic estrogens, including >50 steroidal analogs of E2 and E1, to human ERα and ERβ. Binding affinities of 74 estrogens were measured and a 3‑D quantitative structure‑activity relationship/comparative molecular field analysis of 47 steroidal analogs was performed to identify structural features that determine preferential activation of ERα versus ERβ. The results showed that most metabolites bind ERα and ERβ similarly, but several D‑ring metabolites (e.g., 16α‑hydroxyestradiol, 16β‑hydroxyestradiol‑17α, 16‑ketoestrone) preferentially bind ERβ over ERα by up to 18‑fold, whereas E1 and 2‑hydroxyestrone preferentially bind ERα, indicating that metabolic conversion of E2 can differentially activate ER subtypes and that QSAR analysis revealed structural features guiding this selectivity.

Abstract

To search for endogenous estrogens that may have preferential binding affinity for human estrogen receptor (ER) alpha or beta subtype and also to gain insights into the structural determinants favoring differential subtype binding, we studied the binding affinities of 74 natural or synthetic estrogens, including more than 50 steroidal analogs of estradiol-17beta (E2) and estrone (E1) for human ER alpha and ER beta. Many of the endogenous estrogen metabolites retained varying degrees of similar binding affinity for ER alpha and ER beta, but some of them retained differential binding affinity for the two subtypes. For instance, several of the D-ring metabolites, such as 16 alpha-hydroxyestradiol (estriol), 16 beta-hydroxyestradiol-17 alpha, and 16-ketoestrone, had distinct preferential binding affinity for human ER beta over ER alpha (difference up to 18-fold). Notably, although E2 has nearly the highest and equal binding affinity for ER alpha and ER beta, E1 and 2-hydroxyestrone (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ER alpha over ER beta, whereas 16 alpha-hydroxyestradiol (estriol) and other D-ring metabolites (quantitatively predominant endogenous estrogens formed during pregnancy) have preferential binding affinity for ER beta over ER alpha. Hence, facile metabolic conversion of parent hormone E2 to various metabolites under different physiological conditions may serve unique functions by providing differential activation of the ER alpha or ER beta signaling system. Lastly, our computational three-dimensional quantitative structure-activity relationship/comparative molecular field analysis of 47 steroidal estrogen analogs for human ER alpha and ER beta yielded useful information on the structural features that determine the preferential activation of the ER alpha and ER beta subtypes, which may aid in the rational design of selective ligands for each human ER subtype.