A Combined Ligand- and Structure-Based Virtual Screening Protocol Identifies Submicromolar PPARγPartial Agonists

Dušica Vidović, Scott A. Busby, Patrick R. Griffin, Stephan C. Schürer

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is involved in expression of genes that control glucose and lipid metabolism. PPARγ is the molecular target of the thiazolidinedione (TZD) class of antidiabetic drugs. However, despite their clinical use these drugs are associated with numerous adverse effects, which are related to their full activation of PPARγ transcriptional responses. PPARγ partial agonists are the focus of development efforts towards second-generation PPARγ modulators with favorable pharmacology, potent insulin sensitization without the severe full agonists' adverse effects. In order to identify novel PPARγ partial agonist lead compounds, we developed a virtual screening protocol based on three-dimensional ligand-shape similarity and docking. Prioritization gave 235 compounds for experimental screening from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR)-a chemical library containing 340 000 compounds. Seven novel potent partial agonists were confirmed in cell-based transactivation and competitive binding assays. Our results illustrate a well-designed virtual screening campaign successfully identifying novel lead compounds as potential entry points for the development of antidiabetic drugs.Two heads are better than one! Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) regulates numerous genes involved in obesity and diabetes. PPARγ activated by partial agonists displays desired pharmacological behavior but without the severe side effects associated with the use of known full agonist drugs for the treatment of type 2 diabetes. Virtual screening based on three-dimensional ligand shape similarity and docking identified novel submicromolar PPARγ partial agonists.

Original languageEnglish (US)
Pages (from-to)94-103
Number of pages10
JournalChemMedChem
Volume6
Issue number1
DOIs
StatePublished - Jan 3 2011

Keywords

  • Diabetes
  • Drug design
  • Partial agonists
  • PPARγ
  • Virtual screening

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

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