Medical College of Wisconsin
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Chemical proteomics-based analysis of off-target binding profiles for rosiglitazone and pioglitazone: clues for assessing potential for cardiotoxicity. J Med Chem 2012 Oct 11;55(19):8260-71 PMID: 22970990 PMCID: PMC4113394

Abstract

Drugs exert desired and undesired effects based on their binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target--in this case, PPARĪ³. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with these drugs. Our results suggest that glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity.

Author List

Hoffmann BR, El-Mansy MF, Sem DS, Greene AS

Authors

Andrew S. Greene PhD Interim Vice Chair, Chief, Professor in the Biomedical Engineering department at Medical College of Wisconsin
Brian R. Hoffmann PhD Assistant Professor in the Biomedical Engineering department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Chromatography, Affinity
Gluconeogenesis
Glycolysis
Hypoglycemic Agents
Ion Channels
Lipid Metabolism
Mitochondria
Myocardium
Oxidoreductases
Protein Binding
Proteome
Proteomics
Rats
Synaptic Transmission
Thiazolidinediones



View this publication's entry at the Pubmed website PMID: 22970990
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