A QSAR EVALUATION OF AH RECEPTOR-BINDING OF HALOGENATED AROMATIC XENOBIOTICS

Because of their widespread occurrence and substantial biological acti vity halogenated aromatic hydrocarbons such as polychlorinated bipheny ls (PCBs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-p-dioxins (PCDDs) comprise one of the more important classes o f contaminants in the environment. Some chemicals in this class cause adverse biological effects after binding to an intracellular cytosolic protein called the aryl hydrocarbon receptor (AhR). Toxic responses s uch as thymic atrophy, weight loss, immunotoxicity, and acute lethalit y, as well as induction of cytochrome P4501A1, have been correlated wi th the relative affinity of PCBs, PCDFs, and PCDDs for the AhR. Theref ore, an important step in predicting the effects of these chemicals is the estimation of their binding to the receptor. To date, however, th e use of quantitative structure activity relationship (QSAR) models to estimate binding affinity across multiple chemical classes has shown only modest success possibly due, in part, to a focus on minimum energ y chemical structures as the active molecules. In this study, we evalu ated the use of structural conformations other than those of minimum e nergy for the purpose of developing a model for AhR binding affinity t hat encompasses more of the halogenated aromatic chemicals known to in teract with the receptor. Resultant QSAR models were robust, showing g ood utility across multiple classes of halogenated aromatic compounds.