Faculty of Pharmacy and Pharmaceutical Sciences, University Of Alberta, Edmonton, Alberta, Canada.
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
Med Res Rev. 2018 Mar;38(2):525-555. doi: 10.1002/med.21445. Epub 2017 May 3.
Drug-induced blockade of human ether-a-go-go-related gene (hERG) remains a major impediment in delivering safe drugs to the market. Several drugs have been withdrawn from the market due to their severe cardiotoxic side effects triggered by their off-target interactions with hERG. Thus, identifying the potential hERG blockers at early stages of lead discovery is fast evolving as a standard in drug design and development. A number of in silico structure-based models of hERG have been developed as a low-cost solution to evaluate drugs for hERG liability, and it is now agreed that the hERG blockers bind at the large central cavity of the channel. Nevertheless, there is no clear convergence on the appropriate drug binding modes against the channel. The proposed binding modes differ in their orientations and interpretations on the role of key residues in the channel. Such ambiguities in the modes of binding remain to be a significant challenge in achieving efficient computational predictive models and in saving many important already Food and Drug Administration approved drugs. In this review, we discuss the spectrum of reported binding modes for hERG blockers, the various in silico models developed for predicting a drug's affinity to hERG, and the known successful optimization strategies to avoid off-target interactions with hERG.
药物诱导的人类 Ether-a-go-go 相关基因 (hERG) 阻断仍然是将安全药物推向市场的主要障碍。由于其与 hERG 的非靶点相互作用引发的严重心脏毒性副作用，一些药物已从市场上撤出。因此，在药物发现的早期阶段识别潜在的 hERG 阻断剂已成为药物设计和开发的标准。已经开发了许多基于 hERG 的计算结构模型作为评估药物 hERG 毒性的低成本解决方案，现在已经达成共识，hERG 阻断剂结合在通道的大中央腔中。然而，对于针对通道的适当药物结合模式，尚无明确的共识。提出的结合模式在其取向和对通道中关键残基作用的解释上存在差异。在绑定模式方面的这种歧义仍然是实现高效计算预测模型并挽救许多已获得美国食品和药物管理局批准的重要药物的重大挑战。在这篇综述中，我们讨论了报告的 hERG 阻断剂结合模式的范围、为预测药物与 hERG 的亲和力而开发的各种计算模型，以及已知的成功优化策略，以避免与 hERG 的非靶点相互作用。
