In Silico Identification of Proteins Associated with Drug-induced Liver Injury Based on the Prediction of Drug-target Interactions
In Silico Identification of Proteins Associated with Drug-induced Liver Injury Based on the Prediction of Drug-target Interactions
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DOI：
10.1002/minf.201600142
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发表时间：
2017-07-01
影响因子：
3.6
通讯作者：
Poroikov, Vladimir
中科院分区：
文献类型：
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作者：
Ivanov, Sergey;Semin, Maxim;Poroikov, Vladimir
药物性肝损伤（DILI）是急性肝功能衰竭的主要原因，也是药物退出临床试验和市场的主要原因之一。阐明与DILI相关的分子相互作用可能有助于在药物开发的早期阶段检测潜在的危险药物。本研究的目的是研究与特定人类蛋白质靶点的相互作用可能导致DILI。对包含699种药物信息的数据集进行了与1534种人类蛋白质相互作用的预测，这些药物分为三类DILI：重度（178种药物），中度（310种药物）和无DILI（211种药物）。基于对不同药物类别预测的药物-靶点相互作用的比较，以及使用聚类、基因本体、途径和基因表达分析对这些结果的解释，我们确定了61个与DILI相关的蛋白质靶点。大多数发现的蛋白质与重要细胞过程中断引起的肝细胞死亡以及肝脏炎症的出现有关。结果发现，药物与已确定的靶点的相互作用是大多数药物严重DILI的基本分子机制。因此，与许多已鉴定的靶标相互作用的药物制剂可被认为是在药物研究的早期阶段过滤掉的候选物。
Drug-induced liver injury (DILI) is the leading cause of acute liver failure as well as one of the major reasons for drug withdrawal from clinical trials and the market. Elucidation of molecular interactions associated with DILI may help to detect potentially hazardous pharmacological agents at the early stages of drug development. The purpose of our study is to investigate which interactions with specific human protein targets may cause DILI. Prediction of interactions with 1534 human proteins was performed for the dataset with information about 699 drugs, which were divided into three categories of DILI: severe (178 drugs), moderate (310 drugs) and without DILI (211 drugs). Based on the comparison of drug-target interactions predicted for different drugs' categories and interpretation of those results using clustering, Gene Ontology, pathway and gene expression analysis, we identified 61 protein targets associated with DILI. Most of the revealed proteins were linked with hepatocytes' death caused by disruption of vital cellular processes, as well as the emergence of inflammation in the liver. It was found that interaction of a drug with the identified targets is the essential molecular mechanism of the severe DILI for the most of the considered pharmaceuticals. Thus, pharmaceutical agents interacting with many of the identified targets may be considered as candidates for filtering out at the early stages of drug research.