Thyroid hormone disrupting chemicals (THDCs), often found abundantly in the environment, interfere with normal thyroid hormone signalling 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 THR?1 and the generalised Born solvation model to identify potential THDCs targeting the human THR?1 isoform. The protocol was applied to virtually screen an in-house indoor dust contaminant inventory, yielding 31 dust contaminants as potential THR?1 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 THR?1 binders with binding affinities ranging between 60 ?M and 460 ?M. Molecular dynamics (MD) simulations were employed to examine potential binding modes of these binders and provided a rationale for explaining their specific recognition by THR?1. 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. The authors suggest using the developed structure-based virtual screening protocol to identify and prioritise testing of potential THDCs.
Authors: Zhang J, Li Y, Gupta AA, Nam K, Andersson PL. ;Full Source: Chemical Research in Toxicology. 2016 Jul 13. [Epub ahead of print] ;