Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation
| Autor: | Lídia Cedó, Laura Guasch, Esther Sala, Santiago Garcia-Vallvé, Gerard Pujadas, Markus Muehlbacher, Gerhard Wolber, Klaus R. Liedl, Cristina Valls, Montserrat Pinent, Miquel Mulero, Anna Ardévol, Anna Castell-Auví |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Protein Structure Phytochemistry Drugs and Devices Drug Research and Development Naturwissenschaftliche Fakultät -ohne weitere Spezifikation Databases Pharmaceutical Protein Conformation Phytopharmacology Phytochemicals Drug Evaluation Preclinical lcsh:Medicine Peroxisome proliferator-activated receptor Biology Bioinformatics Biochemistry Partial agonist Mice User-Computer Interface 3T3-L1 Cells Chemical Biology Drug Discovery Macromolecular Structure Analysis Animals Humans Hypoglycemic Agents Drug Partial Agonism Biomacromolecule-Ligand Interactions lcsh:Science chemistry.chemical_classification Biological Products Virtual screening Multidisciplinary lcsh:R Reproducibility of Results Computational Biology Molecular Docking Simulation PPAR gamma Chemistry chemistry ddc:540 Medicine lcsh:Q Medicinal Chemistry Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 11, p e50816 (2012) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0050816 |
| Popis: | BACKGROUND: Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|