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


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.


PPARγ QSAR Docking 



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)


  1. 1.
    Dixit A, Saxena AK (2008) Eur J Med Chem 43(1):73CrossRefGoogle Scholar
  2. 2.
    Rathi L, Kashaw SK, Dixit A, Pandey G, Saxena AK (2004) Bioorg Med Chem 12(1):63CrossRefGoogle Scholar
  3. 3.
    Reaven G (2005) Circulation 112(20):3030CrossRefGoogle Scholar
  4. 4.
    Giaginis C, Theocharis S, Tsantili-Kakoulidou A (2008) Chem Biol Drug Des 72(4):257CrossRefGoogle Scholar
  5. 5.
    Giaginis C, Theocharis S, Tsantili-Kakoulidou A (2009) Mini Rev Med Chem 9(9):1075CrossRefGoogle Scholar
  6. 6.
    Huang HJ, Lee KJ, Yu HW, Chen HY, Tsai FJ, Chen CY (2010) J Biomol Struct Dyn 28(2):187CrossRefGoogle Scholar
  7. 7.
    Iwata Y, Miyamoto S, Takamura M, Yanagisawa H, Kasuya A (2001) J Mol Graph Model 19(6):536CrossRefGoogle Scholar
  8. 8.
    Khanna S, Sobhia ME, Bharatam PV (2005) J Med Chem 48(8):3015CrossRefGoogle Scholar
  9. 9.
    Kumar PM, Hemalatha R, Mahajan SC, Karthikeyan C, Moorthy NS, Trivedi P (2008) Med Chem 4(3):273CrossRefGoogle Scholar
  10. 10.
    Kurogi Y (1999) Drug Des Discov 16(2):109Google Scholar
  11. 11.
    Lather V, Kairys V, Fernandes MX (2009) Chem Biol Drug Des 73(4):428CrossRefGoogle Scholar
  12. 12.
    Liao C, Xie A, Zhou J, Shi L, Li Z, Lu XP (2004) J Mol Model 10(3):165CrossRefGoogle Scholar
  13. 13.
    Rucker C, Scarsi M, Meringer M (2006) Bioorg Med Chem 14(15):5178CrossRefGoogle Scholar
  14. 14.
    Salam NK, Huang TH, Kota BP, Kim MS, Li Y, Hibbs DE (2008) Chem Biol Drug Des 71(1):57CrossRefGoogle Scholar
  15. 15.
    Sundriyal S, Bharatam PV (2009) Eur J Med Chem 44(1):42CrossRefGoogle Scholar
  16. 16.
    Sundriyal S, Viswanad B, Bharathy E, Ramarao P, Chakraborti AK, Bharatam PV (2008) Bioorg Med Chem Lett 18(11):3192CrossRefGoogle Scholar
  17. 17.
    Issemann I, Green S (1990) Nature 347(6294):645CrossRefGoogle Scholar
  18. 18.
    Vedani A, Descloux AV, Spreafico M, Ernst B (2007) Toxicol Lett 173(1):17CrossRefGoogle Scholar
  19. 19.
    Barish GD, Narkar VA, Evans RM (2006) J Clin Invest 116(3):590CrossRefGoogle Scholar
  20. 20.
    Brown JD, Plutzky J (2007) Circulation 115(4):518CrossRefGoogle Scholar
  21. 21.
    Youssef J, Badr M (2004) J Biomed Biotechnol 2004(3):156CrossRefGoogle Scholar
  22. 22.
    Simo R, Rodriguez A, Caveda E (2010) Curr Drug Saf 5(3):234CrossRefGoogle Scholar
  23. 23.
    Stahl M, Guba W, Kansy M (2006) Drug Discov Today 11(7–8):326CrossRefGoogle Scholar
  24. 24.
    Huang CM, Elmets CA, Tang DC, Li F, Yusuf N (2004) Genomics Proteomics Bioinform 2(3):143Google Scholar
  25. 25.
    Desvergne B, Wahli W (1999) Endocr Rev 20(5):649Google Scholar
  26. 26.
    Gasteiger J, Teckentrup A, Terfloth L, Spycher S (2003) J Phys Org Chem 16(4):232CrossRefGoogle Scholar
  27. 27.
    Suh YG, Kim NJ, Koo BW, Lee KO, Moon SH, Shin DH, Jung JW, Paek SM, Chang DJ, Li F, Kang HJ, Le TV, Chae YN, Shin CY, Kim MK, Lim JI, Ryu JS, Park HJ (2008) J Med Chem 51(20):6318CrossRefGoogle Scholar
  28. 28.
    Giaginis C, Theocharis S, Tsantili-Kakoulidou A (2007) J Chromatogr B Analyt Technol Biomed Life Sci 857(2):181CrossRefGoogle Scholar
  29. 29.
    Scarsi M, Podvinec M, Roth A, Hug H, Kersten S, Albrecht H, Schwede T, Meyer UA, Rucker C (2007) Mol Pharmacol 71(2):398CrossRefGoogle Scholar
  30. 30.
    Wishart DS (2008) Pharmacogenomics 9(8):1155CrossRefGoogle Scholar
  31. 31.
    Irwin JJ, Shoichet BK (2005) J Chem Inf Model 45(1):177CrossRefGoogle Scholar
  32. 32.
    Kirchmair J, Markt P, Distinto S, Schuster D, Spitzer GM, Liedl KR, Langer T, Wolber G (2008) J Med Chem 51(22):7021CrossRefGoogle Scholar
  33. 33.
    Cheng Y, Prusoff WH (1973) Biochem Pharmacol 22(23):3099CrossRefGoogle Scholar
  34. 34.
    Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV (1998) Nature 395(6698):137CrossRefGoogle Scholar
  35. 35.
    Han LY, Ma XH, Lin HH, Jia J, Zhu F, Xue Y, Li ZR, Cao ZW, Ji ZL, Chen YZ (2008) J Mol Graph Model 26(8):1276CrossRefGoogle Scholar

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

Personalised recommendations