title: Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor.
abstract: A number of environmental and industrial chemicals are reported to possess androgenic or antiandrogenic activities. These androgenic endocrine disrupting chemicals may disrupt the endocrine system of humans and wildlife by mimicking or antagonizing the functions of natural hormones. The present study developed a low cost recombinant androgen receptor (AR) competitive binding assay that uses no animals. We validated the assay by comparing the protocols and results from other similar assays, such as the binding assay using prostate cytosol. We tested 202 natural, synthetic, and environmental chemicals that encompass a broad range of structural classes, including steroids, diethylstilbestrol and related chemicals, antiestrogens, flutamide derivatives, bisphenol A derivatives, alkylphenols, parabens, alkyloxyphenols, phthalates, siloxanes, phytoestrogens, DDTs, PCBs, pesticides, organophosphate insecticides, and other chemicals. Some of these chemicals are environmentally persistent and/or commercially important, but their AR binding affinities have not been previously reported. To the best of our knowledge, these results represent the largest and most diverse data set publicly available for chemical binding to the AR. Through a careful structure-activity relationship (SAR) examination of the data set in conjunction with knowledge of the recently reported ligand-AR crystal structures, we are able to define the general structural requirements for chemical binding to AR. Hydrophobic interactions are important for AR binding. The interaction between ligand and AR at the 3- and 17-positions of testosterone and R1881 found in other chemical classes are discussed in depth. The SAR studies of ligand binding characteristics for AR are compared to our previously reported results for estrogen receptor binding.
authors.affiliation: Northrop Grumman Information Technology, Jefferson, Arkansas 72079, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Fang
authors.forename: Weida
authors.initials: W
authors.lastname: Tong
authors.forename: William S
authors.initials: WS
authors.lastname: Branham
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Moland
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Dial
authors.forename: Huixiao
authors.initials: H
authors.lastname: Hong
authors.forename: Qian
authors.initials: Q
authors.lastname: Xie
authors.forename: Roger
authors.initials: R
authors.lastname: Perkins
authors.forename: William
authors.initials: W
authors.lastname: Owens
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sheehan
mesh_terms: D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D005485:Flutamide / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007529:Isoflavones / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D019800:Phenol / Q000737:chemistry / Q000378:metabolism; D010795:Phthalic Acids / Q000737:chemistry / Q000378:metabolism; D048789:Phytoestrogens; D028321:Plant Preparations / Q000737:chemistry / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism*; D013256:Steroids / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D001559:Benzhydryl Compounds; D006841:Hydrocarbons, Aromatic; D007529:Isoflavones; D008024:Ligands; D010795:Phthalic Acids; D048789:Phytoestrogens; D028321:Plant Preparations; D011944:Receptors, Androgen; D013256:Steroids; D019800:Phenol; C032279:phthalic acid; D005485:Flutamide; D011078:Polychlorinated Biphenyls; C010129:diphenylmethane