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Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach.
Shengjun Fan1, Qiang Geng, Zhenyu Pan
1State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
BMC Systems Biology
|December 12, 2012
Summary
Torcetrapib, a CETP inhibitor, causes adverse effects. Systems biology identified Platelet-Derived Growth Factor Receptor and Hepatocyte Growth Factor Receptor as potential off-targets, warranting further study.
Area of Science:
- Pharmacology
- Systems Biology
- Bioinformatics
Background:
- Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, increases HDL cholesterol and decreases LDL cholesterol.
- Torcetrapib has been linked to increased mortality and cardiac events.
- The precise mechanisms behind torcetrapib's off-target adverse effects remain unclear.
Purpose of the Study:
- To elucidate the underlying mechanisms of torcetrapib's off-target adverse effects.
- To identify potential molecular targets responsible for torcetrapib's toxicity.
- To utilize a systems biology approach for comprehensive analysis.
Main Methods:
- Developed a systems biology approach integrating human signaling networks and gene expression data.
- Utilized Cytoscape with plugins (BisoGenet, NetworkAnalyzer, ClusterONE) for network construction.
- Applied DAVID and ToppFun for gene ontology and pathway enrichment analysis, and reverse docking for off-target prediction.
Main Results:
- Constructed a large-scale human signaling network (10503 nodes, 47660 relations).
- Identified 388 significantly up-regulated genes in torcetrapib-treated adrenal carcinoma cells.
- Uncovered three key gene regulatory network modules contributing to adverse effects.
- Functional analysis revealed over-representation in cell death, apoptosis, and RNA metabolic processes.
- Pathway analysis implicated PDGFR, HGFR, IL-2 Receptor, and ErbB signaling in adverse cardiovascular effects.
Conclusions:
- Systems biology provides novel insights into torcetrapib's off-target adverse effects.
- Platelet-Derived Growth Factor Receptor (PDGFR), Hepatocyte Growth Factor Receptor (HGFR), IL-2 Receptor, and ErbB tyrosine kinase are highlighted as potential direct off-targets.
- These identified targets require further experimental validation for their role in torcetrapib's toxicity.
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