Identification and Molecular Interaction Studies of Thyroid Hormone Receptor Disruptors among Household Dust Contaminants

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.