Quantitative structure–activity relationships for estrogen receptor binding affinity of phenolic chemicals

Abstract

The estrogen receptor (ER) binding affinities of 25 compounds including 15 industrial phenolic chemicals, two phytoestrogens, three natural steroids and one man-made steroid were detected by a binding competition assay. The 17 industrial phenolic chemicals were selected as objective compounds because they are possibly released from epoxy and polyester–styrene resins used in lacquer coatings of concrete tank and lining of steel pipe in water supply system. A quantitative structure–activity relationship (QSAR) for structurally diverse phenols, nine alkylphenols with only one alkyl group, four hydroxyl biphenyls, bisphenol A and four natural and man-made estrogens was established by applying a quantum chemical modeling method. Logarithm of octanol–water coefficient (log Pow), molecular volume ( V m), and energies of the highest occupied molecular orbital ( ε HOMO) and lowest unoccupied molecular orbital ( ε LUMO) were selected as hydrophobic, steric ( V m), and electronic chemical descriptors, respectively. Chemicals capable of ER binding had large V m and high ε HOMO, while the effects of log Pow and ε LUMO on the binding affinity could not be identified. The QSAR made successful predictions for the three phytoestrogens. Also, the successful prediction of ER-binding affinity for biochanin A, another phytoestrogen, two indicators of pH (phenolphthalin and phenolphthalein) and one alkylphenolic chemical with three alkyl groups (4-methyl-2,6-di-butyl-phenol), by amending the V m in the above-mentioned QSAR according to the electron-density distribution (or HOMO density) is an additional step in the elucidation of chemical steric and electronic parameters for predicting the binding affinities of phenolic compounds.