Estrogenicity of alkylphenolic compounds: A 3-D structure-activity evaluation of gene activation

A structure-activity relationship evaluation of alkylphenol activation of a human estrogen receptor (hER) reporter gene construct was done using the C ommon Reactivity Pattern approach. Energetically reasonable conformer distr ibutions for selected steric and electronic chemical descriptors were prese nted and analyzed. Comparisons of descriptor distributions across active an d nonactive chemicals allowed determination of a common reactivity pattern for hER activation. Chemicals capable of hER binding and gene transcription have high density of O-C{sp(3)} distances, from 6.2 to 6.5 Angstrom; maxim um distances between atoms in the molecule, ranging from 9.9 to 10.1 Angstr om; and a population density on the lowest unoccupied molecular orbital for O-atoms from 0.09 to 0.12 AU. Alkylphenols that were nonactive in the reco mbinant yeast cell assay lacked these stereoelectronic requirements, presum ably precluding receptor occupancy or necessary estrogen response element i nteraction. Derived reactivity patterns were successfully coded into decisi on trees used to screen additional alkylphenols for potential hER activatio n. Successful structure-activity relationship modeling and prediction of ge ne activation for 26 of 29 alkylphenols is an additional step in the elucid ation of chemical steric and electronic three-dimensional parameters that p redict which xenobiotics are likely to be estrogenic and demonstrates a val uable tool for screening and prioritization of chemicals for further testin g.