In Silico Prediction of Human and Rat Liver Microsomal Stability via Machine Learning Methods.

Liver microsomal stability is an important property considered for the screening of drug candidates in the early stage of drug development. Determination of hepatic metabolic stability can be performed by an in vitro assay, but it requires quite a few resources and time. In recent years, machine learning methods have made much progress. Therefore, development of computational models to predict liver microsomal stability is highly desirable in the drug discovery process. In this study, the in silico classification models for the prediction of the metabolic stability of compounds in rat and human liver microsomes were constructed by the conventional machine learning and deep learning methods. The performance of the models was evaluated using the test and external sets. For the rat liver microsomes (RLM) stability, the best model yielded the AUC values of 0.84 and 0.71 on the test and external validation sets, respectively. For the human liver microsome (HLM) stability, the best model exhibited the AUC values of 0.86 and 0.77 on the test and external validation sets, respectively. In addition, several important substructure fragments were detected using information gain and frequency substructure analysis methods. The applicability domain of the models was defined using the Euclidean distance-based method. We anticipate that our results would be helpful for the prediction of liver microsomal stability of compounds in the early stage of drug discovery.