Abstract
Promiscuous inhibition of the human ether-à-go-go-related gene (hERG) potassium channel by drugs poses a major risk for life threatening arrhythmia and costly drug withdrawals. Current knowledge of this phenomenon is derived from a limited number of known drugs and tool compounds. However, in a diverse, naïve chemical library, it remains unclear which and to what degree chemical motifs or scaffolds might be enriched for hERG inhibition. Here we report electrophysiology measurements of hERG inhibition and computational analyses of >300,000 diverse small molecules. We identify chemical ‘communities’ with high hERG liability, containing both canonical scaffolds and structurally distinctive molecules. These data enable the development of more effective classifiers to computationally assess hERG risk. The resultant predictive models now accurately classify naïve compound libraries for tendency of hERG inhibition. Together these results provide a more complete reference map of characteristic chemical motifs for hERG liability and advance a systematic approach to rank chemical collections for cardiotoxicity risk.
Highlights
Potassium currents conducted by the human ether-à-go-go-related gene channel repolarize the membrane during cardiac contraction [1]
Compounds which failed in quality control (QC) include those disrupting cell membranes and those assayed in defective wells in patch plates
We investigated how compounds with in silico classifications of varying accuracy are distributed in the structure network described in Fig. 1, using the distribution of hERG blocker score (hBS) scores and annotated activities to divide the Molecular Library Small Molecule Repository (MLSMR) into three major classes based on predictability: those that are correctly predicted by most models in our ensemble, those that are misclassified by most models, and those with inconsistent votes
Summary
Potassium currents conducted by the human ether-à-go-go-related gene (hERG) channel repolarize the membrane during cardiac contraction [1]. Reduction of hERG current density by unintentional drug block or genetic mutations often slows this repolarization and thereby prolongs the action potential. Because this prolongation increases the QT interval (the time period between de- and repolarization of the ventricular muscles during heartbeat) measured in surface electrocardiogram (ECG), it is commonly termed long QT syndrome (LQTS) [2], which poses significant risk for life-threatening arrhythmias. Global Analysis Reveals Chemical Motifs Enriched for hERG Inhibitors have been withdrawn from the market due to this unintended inhibition [3]. Investigating the hERG effect of candidate drugs has become a critical part of safety assessment
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