|Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach|
|Fan, Shengjun1,2; Geng, Qiang3; Pan, Zhenyu4; Li, Xin1,2; Tie, Lu1,2; Pan, Yan1,2; Li, Xuejun1,2|
|刊名||BMC SYSTEMS BIOLOGY|
|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|
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.
|项目编号||91129727 ; 81020108031 ; 30973558 ; 30901815 ; 30901803 ; 81270049 ; 2009ZX09103-144 ; 2009ZX09301-010 ; B07001|
|资助机构||National Natural Science Foundation of China ; Ministry of Science and Technology in China ; Ministry of Education of China|
|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
|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.|
|APA||Fan, Shengjun.,Geng, Qiang.,Pan, Zhenyu.,Li, Xin.,Tie, Lu.,...&Li, Xuejun.(2012).Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach.BMC SYSTEMS BIOLOGY,6.|
|MLA||Fan, Shengjun,et al."Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach".BMC SYSTEMS BIOLOGY 6(2012).|
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