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

Department of Basic Pharmaceutical Sciences, College of Pharmacy (B.T.Z., G.-Z.H., Y.W., X.-R.J.), University of South Carolina, Columbia, South Carolina 29208; and Julius L. Chambers Biomedical/Biotechnology Research Institute (J.-Y.S.), North Carolina Central University, Durham, North Carolina 27707

Address all correspondence and requests for reprints to: Dr. Bao Ting Zhu, University of South Carolina, Basic Pharmaceutical Sciences, College of Pharmacy, 700 Sumter Street, Columbia, South Carolina 29209. E-mail: btzhu{at}cop.sc.edu.

To search for endogenous estrogens that may have preferential binding affinity for human estrogen receptor (ER) or ß 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-17ß (E₂) and estrone (E₁) for human ER and ERß. Many of the endogenous estrogen metabolites retained varying degrees of similar binding affinity for ER and ERß, but some of them retained differential binding affinity for the two subtypes. For instance, several of the D-ring metabolites, such as 16-hydroxyestradiol (estriol), 16ß-hydroxyestradiol-17, and 16-ketoestrone, had distinct preferential binding affinity for human ERß over ER (difference up to 18-fold). Notably, although E₂ has nearly the highest and equal binding affinity for ER and ERß, E₁ and 2-hydroxyestrone (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ER over ERß, whereas 16-hydroxyestradiol (estriol) and other D-ring metabolites (quantitatively predominant endogenous estrogens formed during pregnancy) have preferential binding affinity for ERß over ER. 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 or ERß signaling system. Lastly, our computational three-dimensional quantitative structure-activity relationship/comparative molecular field analysis of 47 steroidal estrogen analogs for human ER and ERß yielded useful information on the structural features that determine the preferential activation of the ER and ERß subtypes, which may aid in the rational design of selective ligands for each human ER subtype.

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