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Journal of Computer-Aided Molecular Design

, Volume 28, Issue 11, pp 1143–1151 | Cite as

Identification of novel peroxisome proliferator-activated receptor-gamma (PPARγ) agonists using molecular modeling method

  • Veronica M. W. Gee
  • Fiona S. L. Wong
  • Lalitha Ramachandran
  • Gautam Sethi
  • Alan Prem Kumar
  • Chun Wei Yap
Article

Abstract

Peroxisome proliferator-activated receptor-gamma (PPARγ) plays a critical role in lipid and glucose homeostasis. It is the target of many drug discovery studies, because of its role in various disease states including diabetes and cancer. Thiazolidinediones, a synthetic class of agents that work by activation of PPARγ, have been used extensively as insulin-sensitizers for the management of type 2 diabetes. In this study, a combination of QSAR and docking methods were utilised to perform virtual screening of more than 25 million compounds in the ZINC library. The QSAR model was developed using 1,517 compounds and it identified 42,378 potential PPARγ agonists from the ZINC library, and 10,000 of these were selected for docking with PPARγ based on their diversity. Several steps were used to refine the docking results, and finally 30 potentially highly active ligands were identified. Four compounds were subsequently tested for their in vitro activity, and one compound was found to have a K i values of <5 μM.

Keywords

PPARγ QSAR Docking 

Notes

Acknowledgments

This work was supported by the Ministry of Education Academic Research Fund Tier 1 grant [R-148-000-165-112] to CWY. APK is supported by grants from the Singapore Ministry of Education Tier 2 [MOE2012-T2-2-139], Academic Research Fund Tier 1 [R-184-000-228-112], Cancer Science Institute of Singapore, Experimental Therapeutics I Program [Grant R-713-001-011-271], NUHS Bench-to-Beside-Product Grant [184-000-243-515] and John Nott Cancer Fellowship from Cancer Council, Western Australia. GS was supported by grants from National Medical Research Council of Singapore [R-184-000-211-213]. We would like to thank the two reviewers for their insightful and encouraging comments, which helped to improve the quality of our manuscript greatly.

Supplementary material

10822_2014_9791_MOESM1_ESM.xlsx (100 kb)
Supplementary material 1 (XLSX 99 kb)

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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Veronica M. W. Gee
    • 1
  • Fiona S. L. Wong
    • 3
    • 4
  • Lalitha Ramachandran
    • 2
  • Gautam Sethi
    • 2
    • 3
  • Alan Prem Kumar
    • 2
    • 3
    • 5
    • 6
    • 7
  • Chun Wei Yap
    • 1
  1. 1.Department of Pharmacy, Faculty of ScienceNational University of SingaporeSingaporeSingapore
  2. 2.Department of Pharmacology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  3. 3.Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
  4. 4.Department of Biological Sciences, Faculty of ScienceNational University of SingaporeSingaporeSingapore
  5. 5.School of Biomedical Sciences, Faculty of Health SciencesCurtin UniversityBentleyAustralia
  6. 6.Department of Biological SciencesUniversity of North TexasDentonUSA
  7. 7.National University Cancer InstituteSingaporeSingapore

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