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.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
pp. 1617-2615.
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