Global Analysis Reveals Families of Chemical Motifs Enriched for hERG Inhibitors

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.药物对人类ether-à-go-go相关基因（hERG）钾通道的非选择性抑制，会引发致命性心律失常，并导致药物撤市带来高昂成本的重大风险。目前对于这一现象的认知，仅来自有限的已知药物及工具化合物。然而，在多样化的未筛选化学库中，究竟哪些化学基序或骨架更易富集hERG抑制活性，以及其富集程度如何，目前仍不明确。本研究报道了针对hERG抑制活性的电生理学检测结果，以及对超过30万个多样化小分子的计算分析结果。我们鉴定出了具有高hERG风险倾向的化学类群，其中既包含经典骨架分子，也包含结构独特的化合物。这些数据助力开发出更高效的分类器，用于计算评估hERG风险。所得的预测模型如今可精准对未筛选化合物库的hERG抑制倾向进行分类。综上，本研究结果为hERG风险相关的特征性化学基序提供了更为完整的参考图谱，并提出了一套系统性方法，可对化学集合的心脏毒性风险进行排序。