title: Urban Endocrine Disruptors Targeting Breast Cancer Proteins.
abstract: Humans are exposed to a huge amount of environmental pollutants called endocrine disrupting chemicals (EDCs). These molecules interfere with the homeostasis of the body, usually through mimicking natural hormones leading to activation or blocking of their receptors. Many of these compounds have been associated with a broad range of diseases including the development or increased susceptibility to breast cancer, the most prevalent cancer in women worldwide, according to the World Health Organization. Thus, this article presents a virtual high-throughput screening (vHTS) to evaluate the affinity of proteins related to breast cancer, such as ESR1, ERBB2, PGR, BCRA1, and SHBG, among others, with EDCs from urban sources. A blind docking strategy was employed to screen each protein-ligand pair in triplicate in AutoDock Vina 2.0, using the computed binding affinities as ranking criteria. The three-dimensional structures were previously obtained from EDCs DataBank and Protein Data Bank, prepared and optimized by SYBYL X-2.0. Some of the chemicals that exhibited the best affinity scores for breast cancer proteins in each category were 1,3,7,8-tetrachlorodibenzo-p-dioxin, bisphenol A derivatives, perfluorooctanesulfonic acid, and benzo(a)pyrene, for catalase, several proteins, sex hormone-binding globulin, and cytochrome P450 1A2, respectively. An experimental validation of this approach was performed with a complex that gave a moderate binding affinity in silico, the sex hormone binding globulin (SHBG), and bisphenol A (BPA) complex. The protein was obtained using DNA recombinant technology and the physical interaction with BPA assessed through spectroscopic techniques. BPA binds on the recombinant SHBG, and this results in an increase of its α helix content. In short, this work shows the potential of several EDCs to bind breast cancer associated proteins as a tool to prioritize compounds to perform in vitro analysis to benefit the regulation or exposure prevention by the general population.
authors.affiliation: Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, Zaragocilla Campus, University of Cartagena , Cartagena 130015, Colombia.|Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Montes-Grajales
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.|Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Gonçalo J L
authors.initials: GJ
authors.lastname: Bernardes
authors.affiliation: Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, Zaragocilla Campus, University of Cartagena , Cartagena 130015, Colombia.
authors.forename: Jesus
authors.initials: J
authors.lastname: Olivero-Verbel
mesh_terms: D001559:Benzhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001943:Breast Neoplasms / Q000209:etiology; D002374:Catalase / Q000737:chemistry* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry* / Q000378:metabolism; D062126:Databases, Chemical; D030562:Databases, Protein; D004147:Dioxins / Q000737:chemistry / Q000378:metabolism; D052244:Endocrine Disruptors / Q000737:chemistry* / Q000378:metabolism; D004785:Environmental Pollutants / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D006801:Humans; D056004:Molecular Dynamics Simulation; D010636:Phenols / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D012738:Sex Hormone-Binding Globulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D002374:Catalase; D019388:Cytochrome P-450 CYP1A2; D004147:Dioxins; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D010636:Phenols; D011994:Recombinant Proteins; D012738:Sex Hormone-Binding Globulin; C006780:bisphenol A; D000098826:Bisphenol A Compounds