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Using Three-Dimensional Quantitative Structure-Activity Relationships to Examine Estrogen Receptor Binding Affinities of Polychlorinated Hydroxybiphenyls
Chris L. Waller, Deborah L. Minor, and James D. McKinney
Environmental Toxicology Division, Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 USA
Abstract
Certain phenyl-substituted hydrocarbons of environmental concern have the potential to disrupt the endocrine system of animals, apparently in association with their estrogenic properties. Competition with natural estrogens for the estrogen receptor is a possible mechanism by which such effects could occur. We used comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (QSAR) paradigm, to examine the underlying structural properties of ortho-chlorinated hydroxybiphenyl analogs known to bind to the estrogen receptor. The cross-validated and conventional statistical results indicate a high degree of internal predictability for the molecules included in the training data set. In addition to the phenolic (A) ring system, conformational restriction of the overall structure appears to play an important role in estrogen receptor binding affinity. Hydrophobic character as assessed using hydropathic interaction fields also contributes in a positive way to binding affinity. The CoMFA-derived QSARs may be useful in examining the estrogenic activity of a wider range of phenyl-substituted hydrocarbons of environmental concern. Key words: comparative molecular field analysis, estradiol equivalents, estrogen receptor, polychlorinated biphenyls, quantitative structure- activity relationships. Environ Health Perspect 103:702-707 (1995)
Address correspondence to C.L. Waller. D.L. Minor is currently at Molecular Simulations, Inc., Research Triangle Park, NC 27711 USA.
C.L.W. acknowledges support from the Center for Molecular Design, School of Medicine, Washington University, St. Louis, Missouri, and from NIH Cardiovascular Training grant T32HLO7275. This manuscript has been reviewed in accordance with the policy of the Health Effects Research Laboratory, U.S. EPA, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
The coordinates and partial atomic charges for all molecules included in the studies presented here are available from the authors in SYBYL mol2 format as supplementary material.
