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
2), leave-one-out cross validation Q
2 (Q
LOO
2), bootstrapping coefficient (Q
BOOT
2), external
validation coefficient (Q
EXT
2) and concordance correlation coefficient
(CCC) of the developed model met the acceptable criteria
(Q
2 > 0.600, R
2 > 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.
