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学科主题: 基础医学
题名:
Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach
作者: Fan, Shengjun1,2; Geng, Qiang3; Pan, Zhenyu4; Li, Xin1,2; Tie, Lu1,2; Pan, Yan1,2; Li, Xuejun1,2
刊名: BMC SYSTEMS BIOLOGY
发表日期: 2012-12-10
DOI: 10.1186/1752-0509-6-152
卷: 6
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Mathematical & Computational Biology
研究领域[WOS]: Mathematical & Computational Biology
关键词[WOS]: HEPATOCYTE GROWTH-FACTOR ; HIGH-DENSITY-LIPOPROTEIN ; REGULATORY T-CELLS ; LARGE GENE LISTS ; ANGIOTENSIN-II ; FUNCTIONAL-ANALYSIS ; FACTOR RECEPTOR ; ATHEROSCLEROSIS ; PROLIFERATION ; EXPRESSION
英文摘要:

Background: Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor which raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol level, has been documented to increase mortality and cardiac events associated with adverse effects. However, it is still unclear the underlying mechanisms of the off-target effects of torcetrapib.

Results: In the present study, we developed a systems biology approach by combining a human reassembled signaling network with the publicly available microarray gene expression data to provide unique insights into the off-target adverse effects for torcetrapib. Cytoscape with three plugins including BisoGenet, NetworkAnalyzer and ClusterONE was utilized to establish a context-specific drug-gene interaction network. The DAVID functional annotation tool was applied for gene ontology (GO) analysis, while pathway enrichment analysis was clustered by ToppFun. Furthermore, potential off-targets of torcetrapib were predicted by a reverse docking approach. In general, 10503 nodes were retrieved from the integrative signaling network and 47660 inter-connected relations were obtained from the BisoGenet plugin. In addition, 388 significantly up-regulated genes were detected by Significance Analysis of Microarray (SAM) in adrenal carcinoma cells treated with torcetrapib. After constructing the human signaling network, the over-expressed microarray genes were mapped to illustrate the context-specific network. Subsequently, three conspicuous gene regulatory networks (GRNs) modules were unearthed, which contributed to the off-target effects of torcetrapib. GO analysis reflected dramatically over-represented biological processes associated with torcetrapib including activation of cell death, apoptosis and regulation of RNA metabolic process. Enriched signaling pathways uncovered that IL-2 Receptor Beta Chain in T cell Activation, Platelet-Derived Growth Factor Receptor (PDGFR) beta signaling pathway, IL2-mediated signaling events, ErbB signaling pathway and signaling events mediated by Hepatocyte Growth Factor Receptor (HGFR, c-Met) might play decisive characters in the adverse cardiovascular effects associated with torcetrapib. Finally, a reverse docking algorithm in silico between torcetrapib and transmembrane receptors was conducted to identify the potential off-targets. This screening was carried out based on the enriched signaling network analysis.

Conclusions: Our study provided unique insights into the biological processes of torcetrapib-associated off-target adverse effects in a systems biology visual angle. In particular, we highlighted the importance of PDGFR, HGFR, IL-2 Receptor and ErbB1tyrosine kinase might be direct off-targets, which were highly related to the unfavorable adverse effects of torcetrapib and worthy of further experimental validation.

语种: 英语
所属项目编号: 91129727 ; 81020108031 ; 30973558 ; 30901815 ; 30901803 ; 81270049 ; 2009ZX09103-144 ; 2009ZX09301-010 ; B07001
项目资助者: National Natural Science Foundation of China ; Ministry of Science and Technology in China ; Ministry of Education of China
WOS记录号: WOS:000313896600001
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/49962
Appears in Collections:基础医学院_药理学系_期刊论文

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作者单位: 1.Peking Univ, State Key Lab Nat & Biomimet Drugs, Dept Pharmacol, Sch Basic Med Sci, Beijing 100191, Peoples R China
2.Peking Univ, Inst Syst Biomed, Beijing 100191, Peoples R China
3.Peking Univ, Dept Cardiol, Peoples Hosp, Beijing 100044, Peoples R China
4.Xian Childrens Hosp, Dept Pharm, Xian 710003, Peoples R China

Recommended Citation:
Fan, Shengjun,Geng, Qiang,Pan, Zhenyu,et al. Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach[J]. BMC SYSTEMS BIOLOGY,2012,6.
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