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 Several drugs have been withdrawn from the market due to their severe cardiotoxic side effects triggered by their off‐target interactions with hERG.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.

中文翻译：

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安全药物的开发：hERG的挑战

药物诱导的人类以太相关基因（hERG）的封锁仍然是向市场提供安全药物的主要障碍。由于其与hERG的脱靶相互作用引起的严重心脏毒性副作用，一些药物已退出市场。因此，在铅发现的早期阶段识别潜在的hERG阻滞剂正在迅速发展为药物设计和开发的标准。已开发出许多基于计算机模拟的基于结构的hERG模型，作为评估药物对hERG责任的低成本解决方案，现在已经同意，hERG阻滞剂结合在通道的大中央腔中。但是，针对该通道的适当药物结合方式尚无明确的共识。提议的结合模式在其方向和通道中关键残基作用的解释上有所不同。在实现有效的计算预测模型和保存许多已经获得美国食品药品监督管理局批准的重要药物方面，结合方式的这种含糊不清仍然是一个重大挑战。在本文中，我们讨论了已报道的hERG阻断剂结合模式的范围，为预测药物对hERG的亲和力而开发的各种计算机模拟模型，以及避免与hERG脱靶相互作用的已知成功的优化策略。