Journal
TOXICOLOGY LETTERS
Volume 232, Issue 2, Pages 533-541Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2014.12.006
Keywords
Organophosphate flame retardants (OPFRs); p53; Docking; Quantitative structure-activity relationship (QSAR); Binding affinity; Partial least squares (PLS)
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Funding
- National Natural Science Foundation of China [21107136, 21437006]
- International Foundation for Science [F/5230-1]
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Health concerns have been raised in regards to the environmental impact of the more frequently used organophosphate flame retardants (OPFRs). In this study, the effects of two typical OPFRs (TCPP and TPhP) on p53 gene expression in human embryo liver L02 cells were determined by quantitative real-time PCR. To better understand the relationship between molecular structural features of OPFRs and binding affinities for the tumor suppressor genes p53, an integrated experimental and in silico approach was used. The interaction of 9 OPFRs with p53 DNA fragment under simulated physiological conditions (phosphate buffer solution of pH 7.40), was explored by UV absorption spectroscopy, fluorescence spectroscopy and molecular modeling method. The binding constants of 9 OPFRs with p53 DNA fragment were determined respectively, using ethidium bromide (EB) as fluorescence probe of DNA. From docking analysis, hydrogen bonding and hydrophobic interactions were found to be the dominant interactions. Based on the observed interactions, appropriate molecular structural parameters were adopted to develop a quantitative structure-activity relationship (QSAR) model. The binding affinities of OPFRs to p53 DNA fragment were related with molecular electrostatic potential. The developed QSAR model had good robustness, predictive ability and mechanism interpretability. (c) 2014 Elsevier Ireland Ltd. All rights reserved.
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