An increasing number of commonly prescribed drugs are known to interfere with mitochondrial function, which is associated with almost half of all Food and Drug Administration black box warnings, a variety of drug withdrawals, and attrition of drug candidates. This can mainly be attributed to a historic lack of sensitive and specific assays to identify the mechanisms underlying mitochondrial toxicity during drug development. In the last decade, a better understanding of drug-induced mitochondrial dysfunction has been achieved by network-based and structure-based systems pharmacological approaches. Here, we propose the implementation of a tiered systems pharmacology approach to detect adverse mitochondrial drug effects during preclinical drug development, which is based on a toolset developed to study inherited mitochondrial disease. This includes phenotypic characterization, profiling of key metabolic alterations, mechanistic studies, and functional in vitro and in vivo studies. Combined with binding pocket similarity comparisons and bottom-up as well as top-down metabolic network modeling, this tiered approach enables identification of mechanisms underlying drug-induced mitochondrial dysfunction. After validation of these off-target mechanisms, drug candidates can be adjusted to minimize mitochondrial activity. Implementing such a tiered systems pharmacology approach could lead to a more efficient drug development trajectory due to lower drug attrition rates and ultimately contribute to the development of safer drugs.

中文翻译：

---

是时候改变了：解开药物诱导的线粒体毒性机制的系统药理学方法

已知越来越多的常用处方药会干扰线粒体功能，这与食品和药物管理局几乎一半的黑框警告、各种药物撤回和候选药物流失有关。这主要归因于历史上缺乏灵敏和特异性的检测方法来确定药物开发过程中线粒体毒性的潜在机制。在过去十年中，通过基于网络和基于结构的系统药理学方法，对药物引起的线粒体功能障碍有了更好的理解。在这里，我们建议实施分层系统药理学方法来检测临床前药物开发过程中线粒体药物的不良反应，该方法基于为研究遗传性线粒体疾病而开发的工具集。这包括表型表征、关键代谢改变的分析、机制研究以及体外和体内功能研究。结合结合口袋相似性比较和自下而上以及自上而下的代谢网络建模，这种分层方法能够识别药物引起的线粒体功能障碍的潜在机制。在验证这些脱靶机制后，可以调整候选药物以最大限度地减少线粒体活性。由于药物损耗率较低，实施这种分层系统药理学方法可能会导致更有效的药物开发轨迹，并最终有助于开发更安全的药物。结合结合口袋相似性比较和自下而上以及自上而下的代谢网络建模，这种分层方法能够识别药物引起的线粒体功能障碍的潜在机制。在验证这些脱靶机制后，可以调整候选药物以最大限度地减少线粒体活性。由于药物损耗率较低，实施这种分层系统药理学方法可能会导致更有效的药物开发轨迹，并最终有助于开发更安全的药物。结合结合口袋相似性比较和自下而上以及自上而下的代谢网络建模，这种分层方法能够识别药物引起的线粒体功能障碍的潜在机制。在验证这些脱靶机制后，可以调整候选药物以最大限度地减少线粒体活性。由于药物损耗率较低，实施这种分层系统药理学方法可能会导致更有效的药物开发轨迹，并最终有助于开发更安全的药物。可以调整候选药物以最小化线粒体活性。由于药物损耗率较低，实施这种分层系统药理学方法可能会导致更有效的药物开发轨迹，并最终有助于开发更安全的药物。可以调整候选药物以最小化线粒体活性。由于药物损耗率较低，实施这种分层系统药理学方法可能会导致更有效的药物开发轨迹，并最终有助于开发更安全的药物。