title: 3D QSAR studies of hydroxylated polychlorinated biphenyls as potential xenoestrogens.
abstract: Mono-hydroxylated polychlorinated biphenyls (OH-PCBs) are found in human biological samples and lack of data on their potential estrogenic activity has been a source of concern. We have extended our previous in silico 2D QSAR study through the application of advance techniques such as docking and 3D QSAR to gain insights into their estrogen receptor (ERα) binding. The results support our earlier findings that the hydroxyl group is the most important feature on the compounds; its position, orientation and surroundings in the structure are influential for the binding of OH-PCBs to ERα. This study has also revealed the following additional interactions that influence estrogenicity of these chemicals (a) the aromatic interactions of the biphenyl moieties with the receptor, (b) hydrogen bonding interactions of the p-hydroxyl group with key amino acids ARG394 and GLU353, (c) low or no electronegative substitution at para-positions of the p-hydroxyl group, (d) enhanced electrostatic interactions at the meta position on the B ring, and (e) co-planarity of the hydroxyl group on the A ring. In combination the 2D and 3D QSAR approaches have led us to the support conclusion that the hydroxyl group is the most important feature on the OH-PCB influencing the binding to estrogen receptors, and have enhanced our understanding of the mechanistic details of estrogenicity of this class of chemicals. Such in silico computational methods could serve as useful tools in risk assessment of chemicals.
authors.affiliation: Computational Toxicology and Methods Development Laboratory, Division of Toxicology and Human Health Sciences, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road, MS-F57, Atlanta, GA, 30333, USA. Electronic address: pruiz@cdc.gov.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ruiz
authors.affiliation: VLife Sciences Tech. Pvt. Ltd., Plot No-05, Survey No 131/1b/2/11, Ram Indu Park, Baner Road, Pune, 411045, India.
authors.forename: Kundan
authors.initials: K
authors.lastname: Ingale
authors.affiliation: Computational Toxicology and Methods Development Laboratory, Division of Toxicology and Human Health Sciences, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road, MS-F57, Atlanta, GA, 30333, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Wheeler
authors.affiliation: Computational Toxicology and Methods Development Laboratory, Division of Toxicology and Human Health Sciences, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road, MS-F57, Atlanta, GA, 30333, USA.
authors.forename: Moiz
authors.initials: M
authors.lastname: Mumtaz
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D030562:Databases, Protein; D047628:Estrogen Receptor alpha / Q000737:chemistry*; D004968:Estrogens, Non-Steroidal / Q000737:chemistry / Q000633:toxicity*; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D006900:Hydroxylation; D008024:Ligands; D062105:Molecular Docking Simulation; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D020798:Two-Hybrid System Techniques; D015262:Xenobiotics / Q000737:chemistry / Q000633:toxicity*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004968:Estrogens, Non-Steroidal; D008024:Ligands; D015262:Xenobiotics; D011078:Polychlorinated Biphenyls
keywords: 2D QSAR; 3D QSAR; In silico modeling; OH-PCBs; kNN MFA