QUANTITATIVE STRUCTURE–ACTIVITY RELATIONSHIP MODELS FOR PREDICTION OF ESTROGEN RECEPTOR BINDING AFFINITY OF STRUCTURALLY DIVERSE CHEMICALS

2003 ◽  
Vol 22 (8) ◽  
pp. 1844 ◽  
Author(s):  
Patricia K. Schmieder ◽  
Gerald Ankley ◽  
Ovanes Mekenyan ◽  
John D. Walker ◽  
Steven Bradbury
Keyword(s):  
Estrogen Receptor ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Quantitative Structure Activity Relationship ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Quantitative Structure ◽  
Receptor Binding Affinity ◽  
Estrogen Receptor Binding ◽  
Structure Activity

scholarly journals 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

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4132-4150 ◽  
Author(s):  
Bao Ting Zhu ◽  
Gui-Zhen Han ◽  
Joong-Youn Shim ◽  
Yujing Wen ◽  
Xiang-Rong Jiang
Keyword(s):  
Estrogen Receptor ◽  
Binding Affinity ◽  
Quantitative Structure Activity Relationship ◽  
Activity Relationship ◽  
Quantitative Structure ◽  
Structural Determinants ◽  
Structure Activity ◽  
Preferential Binding ◽  
Human Estrogen Receptor ◽  
Endogenous Estrogen

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

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