Using Three-Dimensional Quantitative Structure-Activity Relationships to Examine Estrogen Receptor Binding Affinities of Polychlorinated Hydroxybiphenyls

Abstract

Certain phenyl-substituted hyd ns of environmental concen 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 isaa possible mechanism by which such effects could occur. We used comp molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (QSAR) (11).In addition to the PCB family of chemicals, other phenyl-substituted hydrocarbons such as the biphenyl ethanes and ethylenes related to diethylstilbestrol (DES) (12) and triphenylethanes (13), including tamoxifen and nafoxidine, have been shown to be ligands of the estrogen receptor. A common substructure of many of these chemicals is a phenolic ring system, with an obvious relationship to the phenolic A ring in estradiol (Fig. 1). However, it is not clear if in all cases the hydroxyl group has unique properties as a substituent or if any similar-sized (isosteric) group, such as chlorine, could replace it. Such a substructure serves as a unique way to align the molecules for comparing the overall structures of otherwise structurally diverse chemicals. In this way it may be possible to determine their estradiol equivalency (14) in a manner analogous to determining the dioxin equivalency (15) of structurally related chlorinated aromatic hydrocarbons of environmental health concern. We used comparative molecular field analysis (CoMFA) (16), a three-dimensional quantiative structure-activity relationship (QSAR) paradigm, to examine the unique physicochemical properties of polychlorinated hydroxybiphenyls (Table 1) underlying their estrogen receptor binding affinities and thus their potential estradiol equivalency. MethodsThe SYBYL molecular modeling software package (version 6.0, Tripos Associates, Inc., St. Louis, Missouri) was used to do all molecular modeling. The coordinates for estradiol and DES were retrieved from the Cambridge Structural Database. The remaining molecules were constructed in SYBYL using the sketch option. All molecules were minimized using the standard Tripos force field (17) to an energy change convergence criterion of 0.001 kcal/mol. The SYBYL geometries were used as starting coordinates for full-geometry optimization using MOPAC 5.0 (Quantum Chemistry Program Exchange, Indiana University, Bloomington, Indiana) with the AMI (18) model Hamiltonian.For each biphenyl molecule (including DES), using the MOPAC/AMI optimized structure as a starting point, the conformational space about the twist bond(s) connecting the two ring systems was explored. This bond was systematically searched at 50 increments. The lowest energy conformer obtained from the search was then subjected to full MOPAC/AM1 optimization. This structure was then aligned relative to estradiol by root-mean-squares (RMS) fit of the hydroxyphenyl ring (A) carbons and the corresponding carbons of the para-substituted ring of the molecule to be fitted. Due to structural symmetry of the biphenyls, several alignments w...

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