HERGAI: an artificial intelligence tool for structure-based prediction of hERG inhibitors.

The human Ether-à-go-go-Related Gene (hERG) potassium channel is crucial for repolarizing the cardiac action potential and regulating the heartbeat. Molecules that inhibit this protein can cause acquired long QT syndrome, increasing the risk of arrhythmias and sudden fatal cardiac arrests. Detecting compounds with potential hERG inhibitory activity is therefore essential to mitigate cardiotoxicity risks. In this article, we present a new hERG data set of unprecedented size, comprising nearly 300,000 molecules reported in PubChem and ChEMBL, approximately 2000 of which were confirmed hERG blockers identified through in vitro assays. Multiple structure-based artificial intelligence (AI) binary classifiers for predicting hERG inhibitors were developed, employing, as descriptors, protein-ligand extended connectivity (PLEC) fingerprints fed into random forest, extreme gradient boosting, and deep neural network (DNN) algorithms. Our best-performing model, a stacking ensemble classifier with a DNN meta-learner, achieved state-of-the-art classification performance, accurately identifying 86% of molecules having half-maximal inhibitory concentrations (IC