Molecular structural characteristics as determinants of estrogen receptor selectivity

Agatonovic-Kustrin, S., Turner, J.V., and Glass, B.D. (2008) Molecular structural characteristics as determinants of estrogen receptor selectivity. Journal of Pharmaceutical and Biomedical Analysis, 48 (2). pp. 369-375.

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Abstract

Recent reports that a wide variety of natural and man-made compounds are capable of competing with natural hormones for estrogen receptors serve as timely examples of the need to advance screening techniques to support human health and ascertain ecological risk. Quantitative structure–activity relationships (QSARs) can potentially serve as screening tools to identify and prioritize untested compounds for further empirical evaluations. Computer-based QSAR molecular models have been used to describe ligand–receptor interactions and to predict chemical structures that possess desired pharmacological characteristics. These have recently included combined and differential relative binding affinities of potential estrogenic compounds at estrogen receptors (ER) α and β. In the present study, artificial neural network (ANN) QSAR models were developed that were able to predict differential relative binding affinities of a series of structurally diverse compounds with estrogenic activity. The models were constructed with a dataset of 93 compounds and tested with an additional dataset of 30 independent compounds. High training correlations (r2 = 0.83–0.91) were observed while validation results for the external compounds were encouraging (r2 = 0.62–0.86). The models were used to identify structural features of phytoestrogens that are responsible for selective ligand binding to ERα and ERβ. Numerous structural characteristics are required for complexation with receptors. In particular, size, shape and polarity of ligands, heterocyclic rings, lipophilicity, hydrogen bonding, presence of quaternary carbon atom, presence, position, length and configuration of a bulky side chain, were identified as the most significant structural features responsible for selective binding to ERα and ERβ.

Item ID: 6653
Item Type: Article (Refereed Research - C1)
Keywords: ER-alpha; ER-beta; differntial binding; artificial neural network; QSAR; theoretical descriptors
ISSN: 1873-264X
Date Deposited: 08 Feb 2010 00:34
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9299 Other Health > 929999 Health not elsewhere classified @ 100%
Citation Count from Web of Science Web of Science 10
Downloads: Total: 3
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