title: Computer-aided identification of novel protein targets of bisphenol A.
abstract: The xenoestrogen bisphenol A (2,2-bis-(p-hydroxyphenyl)-2-propane, BPA) is a known endocrine-disrupting chemical used in the fabrication of plastics, resins and flame retardants, that can be found throughout the environment and in numerous every day products. Human exposure to this chemical is extensive and generally occurs via oral route because it leaches from the food and beverage containers that contain it. Although most of the effects related to BPA exposure have been linked to the activation of the estrogen receptor (ER), the mechanisms of the interaction of BPA with protein targets different from ER are still unknown. Therefore, the objective of this work was to use a bioinformatics approach to identify possible new targets for BPA. Docking studies were performed between the optimized structure of BPA and 271 proteins related to different biochemical processes, as selected by text-mining. Refinement docking experiments and conformational analyses were carried out using LigandScout 3.0 for the proteins selected through the affinity ranking (lower than -8.0kcal/mol). Several proteins including ERR gamma (-9.9kcal/mol), and dual specificity protein kinases CLK-4 (-9.5kcal/mol), CLK-1 (-9.1kcal/mol) and CLK-2 (-9.0kcal/mol) presented great in silico binding affinities for BPA. The interactions between those proteins and BPA were mostly hydrophobic with the presence of some hydrogen bonds formed by leucine and asparagine residues. Therefore, this study suggests that this endocrine disruptor may have other targets different from the ER.
authors: Environmental and Computational Chemistry Group, Faculty of Pharmaceutical Sciences, University of Cartagena, Campus of Zaragocilla, Cartagena, Colombia. Electronic address: dmontesg@unicartagena.edu.co.
authors: Diana
authors: D
authors: Montes-Grajales
authors: Jesus
authors: J
authors: Olivero-Verbel
mesh_terms: D001559:Benzhydryl Compounds / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D000090702:Constitutive Androstane Receptor; D052244:Endocrine Disruptors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation / Q000379:methods*; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000187:drug effects* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D000090702:Constitutive Androstane Receptor; D052244:Endocrine Disruptors; D008024:Ligands; D010636:Phenols; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011960:Receptors, Estrogen; C490917:ESRRG protein, human; C000716327:NR1I3 protein, human; C066780:Clk dual-specificity kinases; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: AC50; ADORA2A; AR; BPA; C-C motif chemokine 2; C-X-C motif chemokine 10; CAR(NR1I3); CCL2; CD40; CD69; CLK; CLK1; CLK2; CLK4; CXCL10; CYP1A1; CYP2C19; CYP3A4; Circadian rhythm; DNA topoisomerase 2-alpha; Docking; EAR-7; EDCs; EPA; ER; ERR-gamma; GABA; IHop; Information Hyperlinked over proteins; Interactions; MMP-1; MMP-13; MMP-8; MMP-9; NR3C1; PDB; PGC-1α; PKCθ; PPAR-gamma; Protein Data Bank; R-PTP-epsilon, receptor-type tyrosine-protein phosphatase epsilon; RAR-alpha; RAR-beta; ROR-gamma; RXR-beta; SHBG; SR; TGFB1; TIMP-3; TOP2A; US Environmental Protection Agency; VCAM1; Virtual screening; Xenobiotic; adenosine receptor A2a; androgen receptor; bisphenol A; cdc2-like kinase; constitutive androstane receptor; cytochrome P450 1A1; cytochrome P450 2C19; cytochrome P450 3A4; dual specificity protein kinase CLK1; dual specificity protein kinase CLK2; dual specificity protein kinase CLK4; early activation antigen CD69; endocrine disrupting chemicals; estrogen receptor; estrogen-related receptor gamma; experimental activating concentration 50%; glucocorticoid receptor; matrix metalloproteinase-1; matrix metalloproteinase-13; matrix metalloproteinase-8; matrix metalloproteinase-9; metalloproteinase inhibitor 3; peroxisomal proliferator-activated receptor gamma; proliferator-activated receptor gamma coactivator 1 alpha; protein kinase C theta; retinoic acid receptor RXR-beta; retinoic acid receptor alpha; retinoic acid receptor beta; serine-arginine-rich; sex hormone-binding globulin; thyroid hormone receptor alpha; transforming growth factor beta-1; tumor necrosis factor receptor superfamily member 5; vascular cell adhesion protein 1; γ-aminobutyric acid