Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study.
Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study.
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DOI：
10.1371/journal.pcbi.1002016
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发表时间：
2011-03
影响因子：
4.3
通讯作者：
He L
中科院分区：
文献类型：
--
作者：
Yang L;Wang K;Chen J;Jegga AG;Luo H;Shi L;Wan C;Guo X;Qin S;He G;Feng G;He L
在个性化医疗实践的时代，了解患者特异性药物不良反应（ADR）的遗传基础是一个重大挑战。氯氮平为精神分裂症提供了有效的治疗方法，但由于危及生命的粒细胞缺乏症，其使用受到限制。最近一项影响深远的研究表明，有必要将氯氮平列为一线药物，因此确定药物性粒细胞缺乏症的生物标志物变得非常重要。在这里，我们报告了一种称为反化学-蛋白质相互作用组（CPI）的方法，它利用对接方法来模拟一组人类蛋白质中药物-蛋白质相互作用的差异。利用这种方法，我们确定了HSPA1A，一个已知的CIA易感基因，是氯氮平的脱靶基因。此外，hspa1a相关基因（脱靶相关系统）的mRNA表达也被发现在氯氮平处理的白血病细胞系中存在差异表达。除了确定CIA致病基因外，我们还确定了几个可能导致粒细胞缺乏症的新候选基因。与活性氧清除系统相关的蛋白质，如氧化还原酶和谷胱甘肽代谢物酶，在反相CPI中显著富集。该方法对药物对生物系统的扰动进行了多维度分析，研究了脱靶和相关的脱靶系统，以探索不良事件的分子基础或旧药物的新用途。特异性药物反应（IDR）通常在大量人群服用药物后才能确定，但通常导致限制使用或停药。氯氮平是治疗精神分裂症最有效的药物，但由于危及生命的IDR，即粒细胞缺乏症，氯氮平的使用受到限制。一项高影响的临床研究证明了将氯氮平从三线药物转移到一线药物的必要性；因此，深入的研究旨在确定氯氮平诱导的粒细胞缺乏症（CIA）的基因。奥氮平是氯氮平的类似物，其粒细胞缺乏症的发生率要低得多。基于这一现象，我们提出了一种称为反化学-蛋白质相互作用组（CPI）的计算机方法，该方法模拟了两种药物在一组人类蛋白质中药物-蛋白质相互作用的差异。例如，HSPA1A被确定为氯氮平而不是奥氮平的靶标。此外，氯氮平治疗后hspa1a相关基因系统的基因表达也上调。该方法可以从脱靶和脱靶与药物的相互作用两方面考察系统的扰动，为解码药物不良反应或旧药的新用途提供理论依据。
In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs. Idiosyncratic drug reactions (IDR) generally cannot be identified until after a drug is taken by a large population, but usually result in restricted use or withdrawal. Clozapine provides the most effective treatment for schizophrenia but its use is limited because of a life-threatening IDR, i.e., the agranulocytosis. A high impact clinical study demonstrated the necessity of moving clozapine from 3rd line to 1st line drug; therefore, intensive research has aimed at identifying genes responsible for clozapine-induced agranulocytosis (CIA). Olanzapine, an analog of clozapine, has much lower incidence of agranulocytosis. Based on this phenomenon, we proposed an in silico methodology termed as antithesis chemical-protein interactome (CPI), which mimics the differences in the drug-protein interactions of the two drugs across a panel of human proteins. e.g., HSPA1A was identified to be targeted by clozapine not olanzapine. Furthermore, the gene expression of the HSPA1A-related gene system was also found up-regulated after clozapine treatment. This approach can examine the system's perturbation in terms of both the off-target and the off-system's interaction with the drug, providing theoretical basis for decoding the adverse drug reactions or the new uses for old drugs.
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DOI：
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发表时间：
2011-03
影响因子：
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