应用分子全息QSAR预测多溴二苯醚(PBDEs)的毒性

Holographic quantitative structure-Activity relationship for prediction of the toxicity of polybrominated diphenyl ether congeners

多溴二苯醚(PBDEs)可能会激活芳香烃受体的信号传导通路,从而对人类和野生动物的健康产生负面影响.鉴于多溴二苯醚实验毒性数据有限,发展基于结构的化合物毒性预测模型具有重要的实际意义.本文基于一种新的分子结构表征方法——分子全息,研究了18种多溴二苯醚结构与毒性之间的关系,建立了相关性显著、稳健性强的QSAR模型(r2=0.991,q2LOO=0.917).随机选出14种多溴二苯醚为训练集,其他4种化合物为测试集以验证分子全息QSAR模型的稳健性和预测能力.结果在最佳建模条件下得到模型的统计参数如下:r2=0.988,q2LOO=0.598,r2pred=0.955,预测值与实验值之间的均方根误差(RMSE)为0.155.这表明基于分子全息的QSAR模型可以对多溴二苯醚毒性进行比较准确的预测.本文同时利用分子全息QSAR模型色码图,探讨了影响多溴二苯醚毒性的分子结构特征及分子机理.

Polybrominated diphenyl ether congeners （PBDEs） might activate the AhR signal transduction, and thus might have an adverse effect on the health of humans and wildlife. Because of the limited experimental data, it is important and necessary to develop structure-based models for prediction of the toxicity of the compounds. In this paper, a new molecular structure representation, molecular hologram, was employed to investigate the quantitative relationship between toxicity and molecular structures for 18 PBDEs. The model with the significant correlation and robustness （r2=0.991, q2Loo=0.917） was developed. To verify the robustness and prediction capacity of the derived model, 14 PBDEs were randomly selected from the database as the training set, while the rest were used as the test set. The results generated under modeling conditions the same as the optimal model were as follows： r2=0.988, q2Loo=0.598, r2red =0.955, and RMSE （root-mean-square of errors）=0.155, suggesting the excellent ability of derived model to predict the toxicity of PBDEs. Furthermore, the structural features and molecular mechanism related to the toxicity of PBDEs were explored using HQSAR color coding.