Design, development and evaluation of novel dual PPARδ/PPARγ agonists

Symon Gathiaka, Gayani Nanayakkara, Tracey Boncher, Orlando Acevedo, Johnathon Wyble, Sagar Patel, Akash Patel, Mary Elizabeth Shane, Blake Bonkowski, Jason Wieczorek, Yinghui Rong, Kevin Huggins, Forest Smith, Rajesh H. Amin

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)873-879
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number3
DOIs
StatePublished - Feb 1 2013
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
Assays
Docks
Organelle Biogenesis
Medical problems
Type 2 Diabetes Mellitus
Insulin Resistance
Genes
Insulin
Ligands
Lipids
Polymerase Chain Reaction

Keywords

  • Adiposity
  • AutoDock vina
  • Diabetes
  • Peroxisomal proliferator activating receptor (PPAR)
  • Transciptional activity

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Design, development and evaluation of novel dual PPARδ/PPARγ agonists. / Gathiaka, Symon; Nanayakkara, Gayani; Boncher, Tracey; Acevedo, Orlando; Wyble, Johnathon; Patel, Sagar; Patel, Akash; Shane, Mary Elizabeth; Bonkowski, Blake; Wieczorek, Jason; Rong, Yinghui; Huggins, Kevin; Smith, Forest; Amin, Rajesh H.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 3, 01.02.2013, p. 873-879.

Research output: Contribution to journalArticle

Gathiaka, S, Nanayakkara, G, Boncher, T, Acevedo, O, Wyble, J, Patel, S, Patel, A, Shane, ME, Bonkowski, B, Wieczorek, J, Rong, Y, Huggins, K, Smith, F & Amin, RH 2013, 'Design, development and evaluation of novel dual PPARδ/PPARγ agonists', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 3, pp. 873-879. https://doi.org/10.1016/j.bmcl.2012.11.060
Gathiaka, Symon ; Nanayakkara, Gayani ; Boncher, Tracey ; Acevedo, Orlando ; Wyble, Johnathon ; Patel, Sagar ; Patel, Akash ; Shane, Mary Elizabeth ; Bonkowski, Blake ; Wieczorek, Jason ; Rong, Yinghui ; Huggins, Kevin ; Smith, Forest ; Amin, Rajesh H. / Design, development and evaluation of novel dual PPARδ/PPARγ agonists. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 3. pp. 873-879.
@article{df24a648f79846fa9b99d6b69faccc9a,
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.",
keywords = "Adiposity, AutoDock vina, Diabetes, Peroxisomal proliferator activating receptor (PPAR), Transciptional activity",
author = "Symon Gathiaka and Gayani Nanayakkara and Tracey Boncher and Orlando Acevedo and Johnathon Wyble and Sagar Patel and Akash Patel and Shane, {Mary Elizabeth} and Blake Bonkowski and Jason Wieczorek and Yinghui Rong and Kevin Huggins and Forest Smith and Amin, {Rajesh H.}",
year = "2013",
month = "2",
day = "1",
doi = "10.1016/j.bmcl.2012.11.060",
language = "English (US)",
volume = "23",
pages = "873--879",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "3",

}

TY - JOUR

T1 - Design, development and evaluation of novel dual PPARδ/PPARγ agonists

AU - Gathiaka, Symon

AU - Nanayakkara, Gayani

AU - Boncher, Tracey

AU - Acevedo, Orlando

AU - Wyble, Johnathon

AU - Patel, Sagar

AU - Patel, Akash

AU - Shane, Mary Elizabeth

AU - Bonkowski, Blake

AU - Wieczorek, Jason

AU - Rong, Yinghui

AU - Huggins, Kevin

AU - Smith, Forest

AU - Amin, Rajesh H.

PY - 2013/2/1

Y1 - 2013/2/1

N2 - 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.

AB - 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.

KW - Adiposity

KW - AutoDock vina

KW - Diabetes

KW - Peroxisomal proliferator activating receptor (PPAR)

KW - Transciptional activity

UR - http://www.scopus.com/inward/record.url?scp=84872292832&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872292832&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2012.11.060

DO - 10.1016/j.bmcl.2012.11.060

M3 - Article

C2 - 23273519

AN - SCOPUS:84872292832

VL - 23

SP - 873

EP - 879

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 3

ER -