Human transthyretin binding affinity of halogenated thiophenols and halogenated phenols: An in vitro and in silico study.

Serious harmful effects have been reported for thiophenols, which are widely used industrial materials. To date, little information is available on whether such chemicals can elicit endocrine-related detrimental effects. Herein the potential binding affinity and underlying mechanism of action between human transthyretin (hTTR) and seven halogenated-thiophenols were examined experimentally and computationally. Experimental results indicated that the halogenated-thiophenols, except for pentafluorothiophenol, were powerful hTTR binders. The differentiated hTTR binding affinity of halogenated-thiophenols and halogenated-phenols were observed. The hTTR binding affinity of mono- and di-halo-thiophenols was higher than that of corresponding phenols; while the opposite relationship was observed for tri- and penta-halo-thiophenols and phenols. Our results also confirmed that the binding interactions were influenced by the degree of ligand dissociation. Molecular modeling results implied that the dominant noncovalent interactions in the molecular recognition processes between hTTR and halogenated-thiophenols were ionic pair, hydrogen bonds and hydrophobic interactions. Finally, a model with acceptable predictive ability was developed, which can be used to computationally predict the potential hTTR binding affinity of other halogenated-thiophenols and phenols. Taken together, our results highlighted that more research is needed to determine their potential endocrine-related harmful effects and appropriate management actions should be taken to promote their sustainable use.

Structures of Endocrine-Disrupting Chemicals Determine Binding to and Activation of the Estrogen Receptor α and Androgen Receptor.

Endocrine-disrupting chemicals (EDCs) can interact with nuclear receptors, including estrogen receptor α (ERα) and androgen receptor (AR), to affect the normal endocrine system function, causing severe symptoms. Limited studies queried the EDC mechanisms, focusing on limited chemicals or a set of structurally similar compounds. It remained uncertain how hundreds of diverse EDCs could bind to ERα and AR and cause distinct functional consequences. Here, we employed a series of computational methodologies to investigate the structural features of EDCs that bind to and activate ERα and AR based on more than 4000 compounds. We used molecular docking and molecular dynamics simulations to elucidate the functional consequences and validated structure-function correlations experimentally using a time-resolved fluorescence resonance energy-transfer assay. We found that EDCs share three levels of key fragments. Primary (20 for ERα and 18 for AR) and secondary fragments (38 for ERα and 29 for AR) are responsible for the binding to receptors, and tertiary fragments determine the activity type (agonist, antagonist, or mixed). In summary, our study provides a general mechanism for the EDC function. Discovering the three levels of key fragments may drive fast screening and evaluation of potential EDCs from large sets of commercially used synthetic compounds.