In silico prediction of hERG blockers using machine learning and deep learning approaches

Abstract The human ether‐à‐go‐go‐related gene (hERG) is associated with drug cardiotoxicity. If the hERG channel is blocked, it will lead to prolonged QT interval and cause sudden death in severe cases. Therefore, it is important to evaluate the hERG‐blocking property of compounds in early drug discovery. In this study, a dataset containing 4556 compounds with IC 50 values determined by patch clamp techniques on mammalian lineage cells was collected, and hERG blockers and non‐blockers were distinguished according to three single thresholds and two binary thresholds. Four machine learning (ML) algorithms combining four molecular fingerprints and molecular descriptors as well as graph convolutional neural networks (GCNs) were used to construct a series of binary classification models. The results showed that the best models varied for different thresholds. The ML models implemented by support vector machine and random forest performed well based on Morgan fingerprints and molecular descriptors, with AUCs ranging from 0.884 to 0.950. GCN showed superior prediction performance with AUCs above 0.952, which might be related to its direct extraction of molecular features from the original input. Meanwhile, the classification of binary threshold was better than that of single threshold, which could provide us with a more accurate prediction of hERG blockers. At last, the applicability domain for the model was defined, and seven structural alerts that might generate hERG blockage were identified by information gain and substructure frequency analysis. Our work would be beneficial for identifying hERG blockers in chemicals.