GraphDeep-hERG: Graph Neural Network PharmacoAnalytics for Assessing hERG-Related Cardiotoxicity.

purposeThe human Ether-a-go-go Related-Gene (hERG) encodes rectifying potassium channels that play a significant role during action potential repolarization of cardiomyocytes. Blockade of the hERG channel by off-target drugs can lead to long QT syndrome, significantly increasing the risk of proarrhythmic cardiotoxicity. Traditional hERG screening methods are effort-demanding and time-consuming. Thus, it is essential to develop computational methods to utilize the existing knowledge for faster and more accurate in silico screening. Although with wide use of deep learning/machine learning algorithms, existing computational models often rely on manually defined atomic features to represent atom nodes, which may overlook critical underlying information. Thus, we want to provide a new method to learn the atom representation automatically.

methodsWe first developed an automated atom embedding model using deep neural networks (DNNs), trained with 118,312 compounds collected from the ZINC database. We then trained a Graph neural networks (GNNs) model with 7909 ChEMBL compounds as the classifying part. The integration of our atom embedding model and GNN models formed a classifier that could effectively distinguish between hERG inhibitors and non-inhibitors.

resultsOur atom embedding model achieved 0.93 accuracy in representing structures. Our best GNN model achieved an accuracy of 0.84 and outcompeted traditional machine-learning models, as well as published AI-driven models, in external testing.

conclusionsThese results highlight the potential of our automated atom embedding model as a standard for generating robust molecular representations. Its integration with advanced GNN algorithms offers promising assistance for screening hERG inhibitors and accelerating drug discovery and repurposing.