title: Affinities of organophosphate flame retardants to tumor suppressor gene p53: an integrated in vitro and in silico study.
abstract: 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.
authors.affiliation: Key Laboratory of Coastal Zone Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research (YIC), Chinese Academy of Sciences (CAS), Shandong Provincial Key Laboratory of Coastal Zone Environmental Processes, YICCAS, Yantai, Shandong 264003, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Key Laboratory of Coastal Zone Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research (YIC), Chinese Academy of Sciences (CAS), Shandong Provincial Key Laboratory of Coastal Zone Environmental Processes, YICCAS, Yantai, Shandong 264003, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Linggong Road 2, Dalian 116024, PR China.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Coastal Zone Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research (YIC), Chinese Academy of Sciences (CAS), Shandong Provincial Key Laboratory of Coastal Zone Environmental Processes, YICCAS, Yantai, Shandong 264003, PR China. Electronic address: hfwu@yic.ac.cn.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Wu
mesh_terms: D002460:Cell Line; D003198:Computer Simulation; D004247:DNA / Q000187:drug effects; D053938:DNA Fragmentation; D005411:Flame Retardants / Q000378:metabolism* / Q000633:toxicity*; D016158:Genes, p53 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000378:metabolism* / Q000633:toxicity*; D011485:Protein Binding
chemical_list: D005411:Flame Retardants; D009943:Organophosphorus Compounds; D004247:DNA
keywords: Binding affinity; Docking; Organophosphate flame retardants (OPFRs); Partial least squares (PLS); Quantitative structure–activity relationship (QSAR); p53