title: Identification and Molecular Interaction Studies of Thyroid Hormone Receptor Disruptors among Household Dust Contaminants.
abstract: Thyroid hormone disrupting chemicals (THDCs), often found abundantly in the environment, interfere with normal thyroid hormone signaling and induce physiological malfunctions, possibly by affecting thyroid hormone receptors (THRs). Indoor dust ingestion is a significant human exposure route of THDCs, raising serious concerns for human health. Here, we developed a virtual screening protocol based on an ensemble of X-ray crystallographic structures of human THRβ1 and the generalized Born solvation model to identify potential THDCs targeting the human THRβ1 isoform. The protocol was applied to virtually screen an in-house indoor dust contaminant inventory, yielding 31 dust contaminants as potential THRβ1 binders. Five predicted binders and one negative control were tested using isothermal titration calorimetry, of which four, i.e., 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) ether (BADGE-HCl-H2O), 2,2',4,4'-tetrahydroxybenzophenone (BP2), and 2,4-dichlorophenoxyacetic acid (2,4-D), were identified as THRβ1 binders with binding affinities ranging between 60 μM and 460 μM. Molecular dynamics (MD) simulations were employed to examine potential binding modes of these binders and provided a rationale for explaining their specific recognition by THRβ1. The combination of in vitro binding affinity measurements and MD simulations allowed identification of four new potential THR-targeting THDCs that have been found in household dust. We suggest using the developed structure-based virtual screening protocol to identify and prioritize testing of potential THDCs.
authors.affiliation: Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
authors.forename: Yaozong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
authors.forename: Arun A
authors.initials: AA
authors.lastname: Gupta
authors.affiliation: Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
authors.forename: Kwangho
authors.initials: K
authors.lastname: Nam
authors.affiliation: Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
authors.forename: Patrik L
authors.initials: PL
authors.lastname: Andersson
mesh_terms: D004391:Dust; D052244:Endocrine Disruptors / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000378:metabolism
chemical_list: D004391:Dust; D052244:Endocrine Disruptors; D011988:Receptors, Thyroid Hormone