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

Abstract

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 (IC50s) not exceeding 20 µM in our challenging test set, including 94% of hERG blockers whose IC50s were not greater than 1 µM. It also demonstrated superior screening power compared to virtual screening schemes that used existing scoring functions. This model, named “HERGAI,” along with relevant input/output data and user-friendly source code, is available in our GitHub repository ( https://github.com/vktrannguyen/HERGAI ) and can be used to predict drug-induced hERG blockade, even on large data sets. We present the largest and most complex hERG inhibition data set for AI research, integrating meticulously curated experimental data from PubChem and ChEMBL. This realistic and challenging data set enables the training and evaluation of advanced models for predicting hERG blockers. We also introduce “HERGAI,” a novel stacking ensemble classifier with strong classification and screening performance, leveraging state-of-the-art machine learning/deep learning techniques and incorporating PLEC fingerprints, for the first time, as descriptors of hERG-bound ligand conformations.

Topics & Concepts