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Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence

机译:利用人类遗传学和药理学证据合理化二级药理学筛选

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摘要

Safety-related drug failures remain a major challenge for the pharmaceutical industry. One approach to ensuring drug safety involves assessing small molecule drug specificity by examining the ability of a drug candidate to interact with a panel of “off-target” proteins, referred to as secondary pharmacology screening. Information from human genetics and pharmacology can be used to select proteins associated with adverse effects for such screening. In an analysis of marketed drugs, we found a clear relationship between the genetic and pharmacological phenotypes of a drug’s off-target proteins and the observed drug side effects. In addition to using this phenotypic information for the selection of secondary pharmacology screens, we also show that it can be used to help identify drug off-target protein interactions responsible for drug-related adverse events. We anticipate that this phenotype-driven approach to secondary pharmacology screening will help to reduce safety-related drug failures due to drug off-target protein interactions.
机译:与安全有关的药品故障仍然是制药行业的主要挑战。确保药物安全性的一种方法涉及通过检查候选药物与一组“脱靶”蛋白相互作用的能力来评估小分子药物特异性,这称为二级药理学筛选。来自人类遗传学和药理学的信息可用于选择与不良反应相关的蛋白质进行此类筛选。在对市售药物的分析中,我们发现了药物脱靶蛋白的遗传和药理学表型与观察到的药物副作用之间有明确的关系。除了使用此表型信息来选择次级药理学筛选外,我们还显示它可用于帮助识别造成药物相关不良事件的脱靶蛋白质相互作用。我们预计这种以表型为驱动力的二级药理学筛选方法将有助于减少由于脱靶蛋白相互作用而导致的与安全性相关的药物失败。

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