USING 3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS TO EXAMINE ESTROGEN-RECEPTOR BINDING AFFINITIES OF POLYCHLORINATED HYDROXYBIPHENYLS

Certain phenyl-substituted hydrocarbons of environmental concern have the potential to disrupt the endocrine system of animals, apparently i n association with their estrogenic properties. Competition with natur al estrogens for the estrogen receptor is a possible mechanism by whic h such effects could occur. We used comparative molecular field analys is (CoMFA), a three-dimensional quantitative structure-activity relati onship (QSAR) paradigm, to examine the underlying structural propertie s of ortho-chlorinated hydroxybiphenyl analogs known to bind to the es trogen receptor. The cross-validated and conventional statistical resu lts indicate a high degree of internal predictability for the molecule s included in the training data set. in addition to the phenolic (A) r ing system, conformational restriction of the overall structure appear s to play an important role in estrogen receptor binding affinity. Hyd rophobic character as assessed using hydropathic interaction fields al so contributes in a positive way to binding affinity. The CoMFA-derive d QSARs may be useful in examining the estrogenic activity of a wider range of phenyl-substituted hydrocarbons of environmental concern. com parative molecular field analysis, esrradiol equivalents, estrogen rec eptor, poiychlorinated biphenyls, quantitative structureactivity reiat ionships.