title: Design, development and evaluation of novel dual PPARδ/PPARγ agonists.
abstract: 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.
authors.affiliation: Dept. of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, USA.
authors.forename: Symon
authors.initials: S
authors.lastname: Gathiaka
authors.forename: Gayani
authors.initials: G
authors.lastname: Nanayakkara
authors.forename: Tracey
authors.initials: T
authors.lastname: Boncher
authors.forename: Orlando
authors.initials: O
authors.lastname: Acevedo
authors.forename: Johnathon
authors.initials: J
authors.lastname: Wyble
authors.forename: Sagar
authors.initials: S
authors.lastname: Patel
authors.forename: Akash
authors.initials: A
authors.lastname: Patel
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Shane
authors.forename: Blake
authors.initials: B
authors.lastname: Bonkowski
authors.forename: Jason
authors.initials: J
authors.lastname: Wieczorek
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Rong
authors.forename: Kevin
authors.initials: K
authors.lastname: Huggins
authors.forename: Forest
authors.initials: F
authors.lastname: Smith
authors.forename: Rajesh H
authors.initials: RH
authors.lastname: Amin
mesh_terms: D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015195:Drug Design; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047494:PPAR delta / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D011485:Protein Binding / Q000187:drug effects
chemical_list: D004338:Drug Combinations; D007004:Hypoglycemic Agents; D047494:PPAR delta; D047495:PPAR gamma