title: In Silico Approach To Identify Potential Thyroid Hormone Disruptors among Currently Known Dust Contaminants and Their Metabolites.
abstract: Thyroid hormone disrupting chemicals (THDCs) interfere with the thyroid hormone system and may induce multiple severe physiological disorders. Indoor dust ingestion is a major route of THDCs exposure in humans, and one of the molecular targets of these chemicals is the hormone transporter transthyretin (TTR). To virtually screen indoor dust contaminants and their metabolites for THDCs targeting TTR, we developed a quantitative structure-activity relationship (QSAR) classification model. The QSAR model was applied to an in-house database including 485 organic dust contaminants reported from literature data and their 433 in silico derived metabolites. The model predicted 37 (7.6%) dust contaminants and 230 (53.1%) metabolites as potential TTR binders. Four new THDCs were identified after testing 23 selected parent dust contaminants in a radio-ligand TTR binding assay; 2,2',4,4'-tetrahydroxybenzophenone, perfluoroheptanesulfonic acid, 3,5,6-trichloro-2-pyridinol, and 2,4,5-trichlorophenoxyacetic acid. These chemicals competitively bind to TTR with 50% inhibition (IC50) values at or below 10 μM. Molecular docking studies suggested that these THDCs interacted similarly with TTR via the residue Ser117A, but their binding poses were dissimilar to the endogenous ligand T4. This study identified new THDCs using an in silico approach in combination with bioassay testing and highlighted the importance of metabolic activation for TTR binding.
authors.affiliation: †Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: ‡Institute for Environmental Studies (IVM), VU University Amsterdam, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands.
authors.forename: Jorke H
authors.initials: JH
authors.lastname: Kamstra
authors.affiliation: †Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ghorbanzadeh
authors.affiliation: ‡Institute for Environmental Studies (IVM), VU University Amsterdam, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands.|§Environmental Chemistry Unit, Department of Environmental Science and Analytical Chemistry (ACES), Stockholm University, SE-106 91 Stockholm, Sweden.
authors.forename: Jana M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: ‡Institute for Environmental Studies (IVM), VU University Amsterdam, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands.
authors.forename: Timo
authors.initials: T
authors.lastname: Hamers
authors.affiliation: †Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Patrik L
authors.initials: PL
authors.lastname: Andersson
mesh_terms: D015085:2,4,5-Trichlorophenoxyacetic Acid; D016902:Air Pollution, Indoor / Q000032:analysis; D001665:Binding Sites; D003198:Computer Simulation; D019992:Databases as Topic; D016002:Discriminant Analysis; D004391:Dust / Q000032:analysis*; D052244:Endocrine Disruptors / Q000032:analysis*; D006801:Humans; D020128:Inhibitory Concentration 50; D016018:Least-Squares Analysis; D055442:Metabolome; D062105:Molecular Docking Simulation; D011228:Prealbumin / Q000378:metabolism; D055503:Protein Multimerization; D021281:Quantitative Structure-Activity Relationship; D060388:Support Vector Machine; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: D004391:Dust; D052244:Endocrine Disruptors; D011228:Prealbumin; D013963:Thyroid Hormones; D015085:2,4,5-Trichlorophenoxyacetic Acid