ADMET Evaluation in Drug Discovery. 18. Reliable Prediction of Chemical-Induced Urinary Tract Toxicity by Boosting Machine Learning-Approaches

作者：Lei Tailong; Sun Huiyong; Kang Yu; Zhu Feng; Liu Hui; Zhou Wenfang; Wang Zhe; Li Dan; Li Youyong; Hou Tingjun^*

来源：Molecular Pharmaceutics, 2017, 14(11): 3935-3953.

DOI：10.1021/acs.molpharmaceut.7b00531

• quantitative structure-activity relationship
• urinary tract toxicity
• nephrotoxicity
• imbalanced classification
• boosting
• support vector machine
• ensembles
• machine learning

Xenobiotic chemicals and their metabolites are mainly excreted out of our bodies by the urinary tract through the urine. Chemical-induced urinary tract toxicity is one of the main reasons that cause failure during drug development, and it is a common adverse event for medications, natural supplements, and environmental chemicals. Despite its importance, there are only a few in silico models for assessing urinary tract toxicity for a large number of compounds with diverse chemical structures. Here, we developed a series of qualitative and quantitative structure activity relationship (QSAR) models for predicting urinary tract toxicity. In our study, the recursive feature elimination method incorporated with random forests (RFE-RF) was used for dimension reduction, and then eight machine learning approaches were used for QSAR modeling, i.e., relevance vector machine (RVM), support vector machine (SVM), regularized random forest (RRF), Cs.0 trees, eXtreme gradient boosting (XGBoost), AdaBoost.M1, SVM boosting (SVMBoost), and RVM boosting (RVMBoost). For building classification models, the synthetic minority oversampling technique was used to handle the imbalance data set problem. Among all the machine learning approaches, SVMBoost based on the RBF kernel achieves both the best quantitative (q(ext)(2) = 0.845) and qualitative predictions for the test set (MCC of 0.787, AUC of 0.893, sensitivity of 89.6%, specificity of 94.1%, and global accuracy of 90.8%). The application domains were then analyzed, and all of the tested chemicals fall within the application domain coverage. We also examined the structure features of the chemicals with large prediction errors. In brief, both the regression and classification models developed by the SVMBoost approach have reliable prediction capability for assessing chemical-induced urinary tract toxicity.

• 出版日期2017-11
• 单位浙江大学; 苏州大学