Performance of machine learning algorithms for qualitative and quantitative prediction drug blockade of hERG1 channel

Drug-induced abnormal heart rhythm known as Torsades de Pointes (TdP) is a potential lethal ventricular tachycardia found in many patients. Even newly released anti-arrhythmic drugs, like ivabradine with HCN channel as a primary target, block the hERG potassium current in overlapping concentration interval. Promiscuous drug block to hERG channel may potentially lead to perturbation of the action potential duration (APD) and TdP, especially when combined with polypharmacy and/or electrolyte disturbances. The example of novel anti-arrhythmic ivabradine illustrates clinically important and ongoing deficits in drug design and warrants for better screening methods. There is an urgent need to develop new approaches for rapid and accurate assessment of how drugs with complex interactions and multiple subcellular targets can predispose or protect from drug-induced TdP. One of the unexpected outcomes of compulsory hERG screening implemented in USA and European Union resulted in large datasets of IC50 values for various molecules entering the market. The abundant data allows now to construct predictive machine-learning (ML) models. Novel ML algorithms and techniques promise better accuracy in determining IC50 values of hERG blockade that is comparable or surpassing that of the earlier QSAR or molecular modeling techniques. To test the performance of modern ML techniques, we have developed a computational platform integrating various workflows for quantitative structure activity relationship (QSAR) models using data from the ChEMBL database. To establish predictive powers of ML-based algorithms we computed IC50 values for large dataset of molecules and compared it to automated patch clamp systems for a large dataset of hERG blocking and non-blocking drugs, an industry gold standard in studies of cardiotoxicity. The optimal protocol with high sensitivity and predictive power is based on the novel eXtreme gradient boosting (XGBoost) algorithm. The ML-platform with XGBoost displays excellent performance with a coefficient of determination of up to R2 ∼0.8 for pIC50 values in evaluation datasets, surpassing other metrics and approaches available in literature. Ultimately, the ML-based platform developed in our work is a scalable framework with automation potential to interact with other developing technologies in the cardiotoxicity field, including high-throughput electrophysiology measurements delivering large datasets of profiled drugs, rapid synthesis and drug development via progress in synthetic biology.