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Pure Appl. Chem., 2003, Vol. 75, No. 11-12, pp. 2363-2373

Mechanism-based QSAR approach to the study of the toxicity of endocrine active substances

C. D. Selassie, R. Garg and S. Mekapati

Chemistry Department, Pomona College, Claremont, CA 91711, USA

Abstract: Mechanism-based QSAR models for interactions between various ligands and the estrogenic receptor are developed by using well-developed physicochemical parameters. Common features of these QSARs are identified, and deficiencies in some datasets are highlighted. The relative binding affinities of various substituted hexestrols to estrogen receptors are examined in terms of their steric, electronic, and hydrophobic attributes. Different QSARs for hexestrols and tamoxifens reveal that steric effects are of overriding importance in variations of binding affinity. In the few cases where a large number of diverse substituents are located on aromatic rings, electronic effects emerge and suggest that electron-donating groups enhance binding to the receptor while hydrophobicity plays a marginal role in decreasing binding affinity. With substituted phenols bearing alkyl-type substituents and substituted hydroxy-biphenyls, the binding is strictly dependent on hydrophobicity and size. These QSAR models are described in detail and examined together to illustrate the utility of lateral validation in mechanistic interpretation.