title: Molecular docking revealed potential disruptors of glucocorticoid receptor-dependent reporter gene expression.
abstract: Glucocorticoids are an essential part of the endocrine system that is responsible for a variety of functions such as regulation of immune activity, appropriate brain function, and fetal development. Disturbance of glucocorticoid signaling can lead to various cardiovascular, inflammatory, and autoimmune diseases, so the identification of chemicals that can modulate activity of the glucocorticoid receptor (GR) is crucial. In this study, molecular docking was utilized to find new agonists and antagonists of the GR. The best hits were further tested on the in vitro model of MDA-kb2 cells expressing luciferase activity in a GR-dependent manner. Nine new potential modulators of the receptor, belonging to six structurally diverse classes, were identified. Six of them, tetramethrin and cypermethrin, diethyl hexyl phthalate and diphenyl isophthalate, naphthol AS-OL and dicumyl peroxide, induced luciferase activity; while the other three, bisphenol P, bisphenol M, and Antioxidant 425, suppressed luciferase activity. Of the nine potential GR modulators, only bisphenol M displayed appreciable binding affinity for the receptor.
authors: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors: Katra
authors: K
authors: Kolšek
authors: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors: Martina
authors: M
authors: Gobec
authors: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors: Irena
authors: I
authors: Mlinarič Raščan
authors: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia. Electronic address: marija.sollner@ffa.uni-lj.si.
authors: Marija
authors: M
authors: Sollner Dolenc
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D062126:Databases, Chemical; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006727:Hormone Antagonists / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis* / Q000235:genetics; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection
chemical_list: D052244:Endocrine Disruptors; D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D008156:Luciferases
keywords: Bisphenols; Glucocorticoid receptor; Molecular docking; Phthalates; Pyrethroid insecticide