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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
PubMed
Abstract

Insights

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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