AttenhERG: a Reliable and Interpretable Graph Neural Network Framework for Predicting HERG Channel Blockers

Cardiotoxicity, particularly drug-induced arrhythmias, poses a significant challenge in drug development, highlighting the importance of early-stage prediction of human ether-a-go-go-related gene (hERG) toxicity. hERG encodes the pore-forming subunit of the cardiac potassium channel. Traditional methods are both costly and time-intensive, necessitating the development of computational approaches. In this study, we introduce AttenhERG, a novel graph neural network framework designed to predict hERG channel blockers reliably and interpretably. AttenhERG demonstrates improved performance compared to existing methods with an AUROC of 0.835, showcasing its efficacy in accurately predicting hERG activity across diverse datasets. Additionally, uncertainty evaluation analysis reveals the model's reliability, enhancing its utility in drug discovery and safety assessment. Case studies illustrate the practical application of AttenhERG in optimizing compounds for hERG toxicity, highlighting its potential in rational drug design.Scientific contributionAttenhERG is a breakthrough framework that significantly improves the interpretability and accuracy of predicting hERG channel blockers. By integrating uncertainty estimation, AttenhERG demonstrates superior reliability compared to benchmark models. Two case studies, involving APH1A and NMT1 inhibitors, further emphasize AttenhERG's practical application in compound optimization.