Investigating cardiotoxicity related with hERG channel blockers using molecular fingerprints and graph attention mechanism

Human ether-a-go-go-related gene (hERG) channel blockade by small molecules is a big concern during drug development in the pharmaceutical industry. Failure or inhibition of hERG channel activity caused by drug molecules can lead to prolonging QT interval, which will result in serious cardiotoxicity. Thus, evaluating the hERG blocking activity of all these small molecular compounds is technically challenging, and the relevant procedures are expensive and time-consuming. In this study, we develop a novel deep learning predictive model named DMFGAM for predicting hERG blockers. In order to characterize the molecule more comprehensively, we first consider the fusion of multiple molecular fingerprint features to characterize its final molecular fingerprint features. Then, we use the multi-head attention mechanism to extract the molecular graph features. Both molecular fingerprint features and molecular graph features are fused as the final features of the compounds to make the feature expression of compounds more comprehensive. Finally, the molecules are classified into hERG blockers or hERG non-blockers through the fully connected neural network. We conduct 5-fold cross-validation experiment to evaluate the performance of DMFGAM, and verify the robustness of DMFGAM on external validation datasets. We believe DMFGAM can serve as a powerful tool to predict hERG channel blockers in the early stages of drug discovery and development.