QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS FOR POLYCHLORINATED HYDROXYBIPHENYL ESTROGEN-RECEPTOR BINDING-AFFINITY - AN ASSESSMENT OF CONFORMER FLEXIBILITY

A diverse group of xenobiotics has a high binding affinity to the estr ogen receptor (ER), suggesting that it can accommodate large variabili ty in ligand structure. Relationships between xenobiotic structure, bi nding affinity, and estrogenic response have been suggested to be depe ndent on the conformational structures of the ligands. To explore the influence of conformational flexibility on ER binding affinity, a quan titative structure-activity relationship (QSAR) study was undertaken w ith estradiol, diethylstilbestrol, and a set of polychlorinated hydrox ybiphenyls (PCHBs) of environmental concern. Although the low-energy m inima of the PCHB congeners suggested that interconversions among conf ormers were likely, the electronic parameters associated with the conf ormer geometries for a specific PCHB congener could vary significantly . The results of the QSAR analysis suggested that among the PCHBs stud ied, the most polarizable conformers (lower absolute volume polarizabi lity values) were most closely associated with ER binding affinity. Ac ross the set of ''polarizable'' conformers, which did not include the low-energy gas-phase conformers, the electron donating properties of t he hydroxy moiety and the aromatic component of the estradiol A ring a nalogue in the PCHBs were found to be correlated with higher ER bindin g affinity.