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A REACTIVITY PATTERN OF DISCRIMINATION OF ER AGONISM AND ANTAGONISM BASED ON 3-D MOLECULAR ATTRIBUTES
Citation:
Schmieder, P. K., Y. K. Koleva, AND O. G. Mekenyan. A REACTIVITY PATTERN OF DISCRIMINATION OF ER AGONISM AND ANTAGONISM BASED ON 3-D MOLECULAR ATTRIBUTES. Presented at Quantitative Structure-Activity Relationship 2000 Meeting, Bourgas, Bulgaria, September 16-20, 2000.
Description:
Various models have been developed to predict the relative binding affinity (RBA) of chemicals to estrogen receptors (ER). These models are important for prioritizing chemicals for screening in biological assays assessing the potential for endocrine disruption. One shortcoming of models predicting RBA has been the failure to distinguish potential receptor antagonism from agonism, with resulting inability to predict the type of estrogenic response anticipated. It has been suggested that steroid receptor antagonists are less compact than agonists, thus ER binding of antagonists may prohibit proper alignment of receptor protein helices preventing subsequent transactivation. The current study tests the theory of chemical bulk as a defining parameter of antagonism by employing a 3-D structural approach for development of reactivity patterns for ER ligands (17 agonists, 7 antagonists), molecular parameters examined that were previously found to be associated with ER binding affiinity, namely global (Ehomo) and local (donor delocalizabillities and charges) electron donating ability of insufficient to discriminate ER antagonists from agonists. However, parameters related to molecular bulkiness, including solvent accessible surface and negatively charged Van der Waal's surface, provided reactivity patterns that were 100% successful in discriminating antagonists from agonists in the limited data set tested. Using this preliminary model it is possible to predict additional structures to be tested for their ability to bind but inactivate the ER, providing a further tool for hypothesis testing to elucidate chemical structural characteristics associated with in vivo estrogenicity and anti-estrogenicity.