Design, development and evaluation of novel dual PPARδ/PPARγ agonists
| Autor: | Tracey Boncher, Forest Smith, Jason Wieczorek, Sagar Patel, Kevin W. Huggins, Rajesh Amin, Johnathon Wyble, Mary Elizabeth Shane, Gayani Nanayakkara, Symon Gathiaka, Yinghui Rong, Akash Patel, Blake Bonkowski, Orlando Acevedo |
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| Rok vydání: | 2013 |
| Předmět: |
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Molecular Agonist medicine.drug_class Clinical Biochemistry Pharmaceutical Science Pharmacology Biochemistry PPAR agonist Drug Discovery medicine Hypoglycemic Agents PPAR delta Molecular Biology Gene Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry In vitro toxicology AutoDock Molecular Docking Simulation PPAR gamma Drug Combinations Real-time polymerase chain reaction Mitochondrial biogenesis Docking (molecular) Drug Design Molecular Medicine Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:873-879 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2012.11.060 |
| Popis: | Type 2 diabetes is at epidemic proportions and thus development of novel pharmaceutical therapies for improving insulin sensitivity has become of paramount importance. The objectives of the current study were to develop novel dual PPARγ/δ agonists without the deleterious side effects associated with full PPARγ agonists. Docking simulations of 23 novel compounds within the ligand binding domain of PPARγ/δ were performed using AutoDock Vina which consistently reproduced experimental binding poses from known PPAR agonists. Comparisons were made and described with other docking programs AutoDock and Surflex-Dock (from SYBYL-X). Biological evaluation of compounds was accomplished by transcriptional promoter activity assays, quantitative PCR gene analysis for known PPARγ/δ targets as well as in vitro assays for lipid accumulation and mitochondrial biogenesis verses known PPAR agonists. We found one (compound 9) out of the 23 compounds evaluated, to be the most potent and selective dual PPARγ/δ agonist which did not display the deleterious side effects associated with full PPARγ agonists. |
| Databáze: | OpenAIRE |
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