Emerging Polar Phenolic Disinfection Byproducts Are High-Affinity Human Transthyretin Disruptors: An in Vitro and in Silico Study.

Phenolic disinfection byproducts (phenolic-DBPs) have been identified in recent years. However, the toxicity data for phenolic-DBPs are scarce, hampering their risk assessment and the development of regulations on the acceptable concentration of phenolic-DBPs in water. In this study, the binding potency and underlying interaction mechanism between human transthyretin (hTTR) and five groups of representative phenolic-DBPs (2,4,6-trihalo-phenols, 2,6-dihalo-4-nitrophenols, 3,5-dihalo-4-hydroxybenzaldehydes, 3,5-dihalo-4-hydroxybenzoic acids, halo-salicylic acids) were determined and probed by competitive fluorescence displacement assay integrated with in silico methods. Experimental results implied that 2,4,6-trihalo-phenols, 2,6-dihalo-4-nitrophenols, and 3,5-dihalo-4-hydroxybenzaldehydes have a high binding affinity with hTTR. The hTTR binding potency of the chemicals with electron-withdrawing groups on their molecular structures were higher than that with electron-donor groups. Molecular modeling methods were used to decipher the binding mechanism between model compounds and hTTR. The results documented that ionic pair, hydrogen bonding and hydrophobic interactions were dominant interactions. Finally, a mechanism-based model for predicting the hTTR binding affinity was developed. The determination coefficient ( R), leave-one-out cross validation Q ( Q), bootstrapping coefficient ( Q), external validation coefficient ( Q) and concordance correlation coefficient ( CCC) of the developed model met the acceptable criteria ( Q > 0.600, R > 0.700, CCC > 0.850), implying that the model had good goodness-of-fit, robustness, and external prediction performances. All the results indicated that the phenolic-DBPs have the hTTR disrupting effects, and further studies are needed to investigate their other mechanism of endocrine disruption.