Evaluation ofthe Influence of Halogenation on theBinding of Bisphenol A tothe Estrogen-Related Receptor γ
2020
Halogenation of organic compounds
is one the most important transformations
in chemical synthesis and is used for the production of various industrial
products. A variety of halogenated bisphenol analogs have recently
been developed and are used as alternatives to bisphenol A (BPA),
which is a raw material of polycarbonate that has adverse effects
in animals. However, limited information is available on the potential
toxicity of the halogenated BPA analogs. In the present study, to
assess the latent toxicity of halogenated BPA analogs, we evaluated
the binding and transcriptional activities of halogenated BPA analogs
to the estrogen-related receptor γ (ERRγ), a nuclear receptor
that contributes to the growth of nerves and sexual glands. Fluorinated
BPA analogs demonstrated strong ERRγ binding potency, and inverse
antagonistic activity, similar to BPA. X-ray crystallography and fragment
molecular orbital (FMO) calculation revealed that a fluorine-substituted
BPA analog could interact with several amino acid residues of ERRγ-LBD,
strengthening the binding affinity of the analogs. The ERRγ
binding affinity and transcriptional activity of the halogenated BPAs
decreased with the increase in the size and number of halogen atom(s).
The IC50 values, determined by the competitive binding
assay, correlated well with the binding energy obtained from the docking
calculation, suggesting that the docking calculation could correctly
estimate the ERRγ binding potency of the BPA analogs. These
results confirmed that ERRγ has a ligand binding pocket that
fits very well to BPA. Furthermore, this study showed that the binding
affinity of the BPA analogs can be predicted by the docking calculation,
indicating the importance of the calculation method in the risk assessment
of halogenated compounds.
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