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Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity : a combined virtual screening and biological assay approach

Scarsi, M. and Podvinec, M. and Roth, A. and Hug, H. and Kersten, S. and Albrecht, H. and Schwede, T. and Meyer, U. A. and Rucker, C.. (2007) Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity : a combined virtual screening and biological assay approach. Molecular pharmacology, Vol. 71, H. 2. pp. 398-406.

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Official URL: http://edoc.unibas.ch/dok/A5259305

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Abstract

Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Schwede)
05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Research IT (Podvinec)
UniBasel Contributors:Podvinec, Michael and Schwede, Torsten
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Academic Press
ISSN:0026-895X
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Sep 2012 06:49
Deposited On:22 Mar 2012 13:29

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