title: In silico identification and pharmacological evaluation of novel endocrine disrupting chemicals that act via the ligand-binding domain of the estrogen receptor α.
abstract: Endocrine disrupting chemicals (EDCs) pose a significant threat to human health, society, and the environment. Many EDCs elicit their toxic effects through nuclear hormone receptors, like the estrogen receptor α (ERα). In silico models can be used to prioritize chemicals for toxicological evaluation to reduce the amount of costly pharmacological testing and enable early alerts for newly designed compounds. However, many of the current computational models are overly dependent on the chemistry of known modulators and perform poorly for novel chemical scaffolds. Herein we describe the development of computational, three-dimensional multi-conformational pocket-field docking, and chemical-field docking models for the identification of novel EDCs that act via the ligand-binding domain of ERα. These models were highly accurate in the retrospective task of distinguishing known high-affinity ERα modulators from inactive or decoy molecules, with minimal training. To illustrate the utility of the models in prospective in silico compound screening, we screened a database of over 6000 environmental chemicals and evaluated the 24 top-ranked hits in an ERα transcriptional activation assay and a differential scanning fluorimetry-based ERα binding assay. Promisingly, six chemicals displayed ERα agonist activity (32nM-3.98μM) and two chemicals had moderately stabilizing effects on ERα. Two newly identified active compounds were chemically related β-adrenergic receptor (βAR) agonists, dobutamine, and ractopamine (a feed additive that promotes leanness in cattle and poultry), which are the first βAR agonists identified as activators of ERα-mediated gene transcription. This approach can be applied to other receptors implicated in endocrine disruption.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093 ikufareva@ucsd.edu ruben@ucsd.edu.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: McRobb
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093 ikufareva@ucsd.edu ruben@ucsd.edu.
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093 ikufareva@ucsd.edu ruben@ucsd.edu.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019295:Computational Biology; D052244:Endocrine Disruptors / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000235:genetics; D055772:Green Chemistry Technology; D006801:Humans; D008024:Ligands; D049409:Luciferases, Firefly / Q000235:genetics; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010957:Plasmids; D011485:Protein Binding; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D008024:Ligands; D049409:Luciferases, Firefly
keywords: bisphenol A (BPA); endocrine disrupting chemicals; estrogen receptor α; green chemistry; molecular docking; virtual ligand screening