Hormone Activity of Hydroxylated Polybrominated Diphenyl Ethers on Human Thyroid Receptor-β: In Vitro and In Silico Investigations

Abstract

BackgroundHydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disrupt thyroid hormone status because of their structural similarity to thyroid hormone. However, the molecular mechanisms of interactions with thyroid hormone receptors (TRs) are not fully understood.ObjectivesWe investigated the interactions between HO-PBDEs and TRβ to identify critical structural features and physicochemical properties of HO-PBDEs related to their hormone activity, and to develop quantitative structure–activity relationship (QSAR) models for the thyroid hormone activity of HO-PBDEs.MethodsWe used the recombinant two-hybrid yeast assay to determine the hormone activities to TRβ and molecular docking to model the ligand–receptor interaction in the binding site. Based on the mechanism of action, molecular structural descriptors were computed, selected, and employed to characterize the interactions, and finally a QSAR model was constructed. The applicability domain (AD) of the model was assessed by Williams plot.ResultsThe 18 HO-PBDEs tested exhibited significantly higher thyroid hormone activities than did PBDEs (p < 0.05). Hydrogen bonding was the characteristic interaction between HO-PBDE molecules and TRβ, and aromaticity had a negative effect on the thyroid hormone activity of HO-PBDEs. The developed QSAR model had good robustness, predictive ability, and mechanism interpretability.ConclusionsHydrogen bonding and electrostatic interactions between HO-PBDEs and TRβ are important factors governing thyroid hormone activities. The HO-PBDEs with higher ability to accept electrons tend to have weak hydrogen bonding with TRβ and lower thyroid hormone activities.

In Silico Investigation of the Thyroid Hormone Activity of Hydroxylated Polybrominated Diphenyl Ethers

“…These properties were revealed by employing molecular docking and by developing the quantitative structure−activity relationship (QSAR) model. 20 Similar results were also obtained through the ligand-and receptor-based 3D-QSAR models. 30 However, the model performance should be improved for predictive applications, and further analysis for the mechanism of activity is also required.…”

Noncovalent interactions between hydroxylated polycyclic aromatic hydrocarbon and DNA: Molecular docking and QSAR study

“…Cross-validation simulates how well a model predicts new data, and gives a statistical Q 2 CUM (the fraction of the total variation of the dependent variables that can be predicted by all the extracted components) for the final model. The PLS analysis was performed repeatedly so as to eliminate redundant molecular structural parameters, as done in the previous studies (Chen et al, 2004;Li et al, 2010a).…”

“…However, the standard samples are limited with respect to making experimental determinations of the binding constants (K b ) of each HOPAHs to DNA. Therefore, an alternative approach, quantitative structure-activity relationship (QSAR), is suggested by the new EU chemicals legislation REACH (European Commission., 2002), which has been successfully used in acute toxicity studies (Christen et al, 2010;Li et al, 2010b), mixture toxicity (Arrhenius et al, 2004;Neuwoehner et al, 2010), endocrine disrupting activities (Li et al, , 2010a) and photo-induced toxicity (Wang et al, 2009b;Zhang et al, 2010) of organic compounds.…”

An exploration of the estrogen receptor transcription activity of capsaicin analogues via an integrated approach based on in silico prediction and in vitro assays

“…According to the report issued by the U.S. National Research Council (NRC) in 2007, in vitro assays combined with in silico prediction are recommended for present toxicity exploration (Andersen and Krewski, 2009;Collins et al, 2008). Molecular docking, quantitative structure-activity relationship (QSAR) models, and well-designed in vitro analysis have been successfully used in identifying and predicting structural features that contribute to the interaction between chemicals and nuclear receptors (Li et al, 2010;Mu et al, 2011). It was reported that capsaicin and capsazepine can not only block tumor necrosis factor-␣-induced nuclear factor ÄB activation but also inhibit aromatase activity by different in vitro assays using human cells, and their corresponding binding affinity with aromatase and nuclear factor ÄB were further delineated by molecular docking (Luqman et al, 2011).…”