Applying 3 Dimension-Quantitative Structure Activity Relationship Coupled with FlexX Docking to Predict Estrogenicity of Polybrominated Diphenyl Ethers (PBDEs), Metabolites of PBDEs and Polybrominated Bisphenol A Compounds

摘要

Concentrations of polybrominated diphenyl ethers (PBDEs) and polybrominated bisphenol A (PBBPA) are increasing in the environment and may cause long-term health problems in human. Also, while metabolites of PBDEs are detected in various organisms, little is known about their potential toxicity. Moreover, mechanisms of toxicity of PBDEs and their metabolites are poorly understood and information on the toxicity of most congeners is scarce. Here three-dimensional quantitative structure activity relationships (3D-QSAR) to predict binding to the estrogen receptor (ER) are given. The models have excellent cross-validation Q~2 and R`2 values of 0.848 and 0.996 for the CoMFA model and 0.863 and 0.977 for the CoMSIA model. These models, based on calculated structural indices and a reported experimental toxicology index (relative estrogenic potencies to estradiol, I), were developed for 13 PBDEs, PBBPAs or their metabolites. These two QSAR models were then used to predict the pI (-logI) values of 34 PBDEs, 14 metabolites of PBDEs and 2 (brominated) bisphenol A that have been detected in the environment, but for which empirical values for ER binding are unavailable. Moreover, FlexX, a docking model, was applied to simulate the binding of compounds and estrogen receptor (ER) to gain an insight into the structural and physicochemical features influencing the interaction between compounds and ER, and validate the results of CoMFA and CoMSIA.