Skip to main content

Advertisement

SpringerLink
Log in

Identification of Selective PPAR-γ Modulators by Combining Pharmacophore Modeling, Molecular Docking, and Adipogenesis Assay

  • Original Article
  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

The clinically used glitazones (rosiglitazone and pioglitazone) for type 2 diabetes mellitus therapy have been linked to serious side effects such as fluid retention, congestive heart failure, weight gain, bone loss, and an increased risk of bladder cancer. The complete activation of PPAR-γ receptors in target tissues is linked to these effects. Many studies have demonstrated that partial PPAR-γ activators (GW0072, PAT5A, GQ16) give equivalent therapeutic benefits to full PPAR-γ agonists without the associated side effects. These breakthroughs cleared the path for the development of partial agonists or selective PPAR-γ modulators (SPPARγMs). This study combined pharmacophore modeling, molecular docking, and an adipogenesis experiment to identify thiazolidine analogs as SPPARMs/partial agonists. A custom library of 220 molecules was created and virtual screened to discover 90 compounds as SPPARγMs/ partial agonists. The chosen eight compounds were synthesized and tested for adipogenesis using 3T3L1 cell lines. These compounds’ partial agonistic activity was evaluated in 3T3L1 cell lines by comparing their capacity to stimulate PPAR-γ mediated adipogenesis to that of a full agonist, rosiglitazone. The findings of the adipogenesis experiment demonstrate that all eight compounds examined had a partial potential to stimulate adipogenesis when compared to the full agonist, rosiglitazone. The current investigation identified eight possible PPAR-γ partial agonists or SPPARγMs that may be effective in the treatment of type 2 diabetes mellitus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

ADME:

Absorption, distribution, metabolism, and elimination

AF-2:

Activation factor-2

AUAC:

Area under the accumulation curve

BEDROC:

Boltzmann-enhanced discrimination of ROC

DEX:

Dexamethasone

DIAD:

Diisopropyl azodicarboxylate

DMEM:

Dulbecco’s modified Eagle medium

DMSO:

Dimethyl sulfoxide

EF1%:

Enrichment factor 1%

FBS:

Fetal bovine serum

IBMX:

3-Isobutyl-1-methylxanthine

LBD:

Ligand binding domain

PPARs:

Peroxisome proliferator-activated receptors

PPh3:

Triphenylphosphine

ROC:

Receiver operating characteristic

SDS:

Sodium dodecyl sulfate

SPPARγMs:

Selective PPAR-γ modulators

T2DM:

Type 2 diabetes mellitus

THF:

Tetrahydrofuran

TZDs:

Thiazolidinediones

VS:

Virtual screening

XP:

Extra precision

References

  1. Tenenbaum, A., Fisman, E. Z., & Motro, M. (2003). Metabolic syndrome and type 2 diabetes mellitus: Focus on peroxisome proliferator activated receptors (PPAR). Cardiovascular Diabetology, 2, 4.

    Article  Google Scholar 

  2. Wang, S., Lin, Y., Gao, L., Yang, Z., Lin, J., Ren, S., Li, F., Chen, J., Wang, Z., Dong, Z., Sun, P., & Wu, B. (2022). PPAR-gamma integrates obesity and adipocyte clock through epigenetic regulation of Bmal1. Theranostics, 12, 1589–1606.

    Article  CAS  Google Scholar 

  3. Tan, Y., Muise, E. S., Dai, H., Raubertas, R., Wong, K. K., Thompson, G. M., Wood, H. B., Meinke, P. T., Lum, P. Y., & Thompson, J. R. (2012). Novel transcriptome profiling analyses demonstrate that selective peroxisome proliferator-activated receptor γ (PPARγ) modulators display attenuated and selective gene regulatory activity in comparison with PPARγ full agonists. Molecular Pharmacology, 82, 68–79.

    Article  CAS  Google Scholar 

  4. Tontonoz, P., Hu, E., & Spiegelman, B. M. (1994). Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell, 79, 1147–1156.

    Article  CAS  Google Scholar 

  5. Knouff, C., & Auwerx, J. (2004). Peroxisome proliferator-activated receptor-γ calls for activation in moderation: Lessons from genetics and pharmacology. Endocrine Reviews, 25, 899–918.

    Article  CAS  Google Scholar 

  6. Helal, M., Ali, M. A., Nadrin, A. H., Awad, Y. I., Younis, N. K., Alasyed, B. M., Jamal, M., Eid, D. H., Soliman, H. A., Eissa, S. A. and Ragab, M. (2022). Association between IRS-1, PPAR-gamma and LEP genes polymorphisms and growth traits in rabbits. Anim Biotechnol, 1–9.

  7. Lange, N. F., Graf, V., Caussy, C. & Dufour, J. F. (2022). PPAR-targeted therapies in the treatment of non-alcoholic fatty liver disease in diabetic patients. International Journal Molecular Science, 23.

  8. Teixeira, C., Sousa, A. P., Santos, I., Rocha, A. C., Alencastre, I., Pereira, A. C., Martins-Mendes, D., Barata, P., Baylina, P. & Fernandes, R. (2022). Enhanced 3T3-L1 differentiation into adipocytes by pioglitazone pharmacological activation of peroxisome proliferator activated receptor-gamma (PPAR-gamma). Biology (Basel), 11.

  9. Faghfouri, A. H., Khajebishak, Y., Payahoo, L., Faghfuri, E., & Alivand, M. (2021). PPAR-gamma agonists: Potential modulators of autophagy in obesity. European Journal of Pharmacology, 912, 174562.

    Article  CAS  Google Scholar 

  10. Liu, C., Xiong, Q., Li, Q., Lin, W., Jiang, S., Zhang, D., Wang, Y., Duan, X., Gong, P., & Kang, N. (2022). CHD7 regulates bone-fat balance by suppressing PPAR-gamma signaling. Nature Communications, 13, 1989.

    Article  CAS  Google Scholar 

  11. Soccio, R. E., Chen, E. R., & Lazar, M. A. (2014). Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell metabolism, 20, 573–591.

    Article  CAS  Google Scholar 

  12. Yokoi, T. (2010), in Adverse drug reactions: Handbook of Experimental Pharmacology, 419–435.

  13. Kroker, A. J., & Bruning, J. B. (2015). Review of the structural and dynamic mechanisms of PPARγpartial agonism. PPAR Research, 2015, 1–15.

    Article  Google Scholar 

  14. Jaeschke, H. (2007). Troglitazone hepatotoxicity: Are we getting closer to understanding idiosyncratic liver injury? Toxicological Sciences, 97, 1–3.

    Article  CAS  Google Scholar 

  15. Cheng, D., Gao, H. & Li, W. (2018). Wpływ długotrwałego stosowania rozyglitazonu na zdarzenia sercowo-naczyniowe — przegląd systematyczny i metaanaliza. Endokrynologia Polska, 69.

  16. Ryder, R. E. J. (2015). Pioglitazone has a dubious bladder cancer risk but an undoubted cardiovascular benefit. Diabetic Medicine, 32, 305–313.

    Article  CAS  Google Scholar 

  17. Korhonen, P., Heintjes, E. M., Williams, R., Hoti, F., Christopher, S., Majak, M., Kool-Houweling, L., Strongman, H., Linder, M., Dolin, P. and Bahmanyar, S. (2016) Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries. Bmj.

  18. Ferwana, M., Firwana, B., Hasan, R., Al-Mallah, M. H., Kim, S., Montori, V. M., & Murad, M. H. (2013). Pioglitazone and risk of bladder cancer: A meta-analysis of controlled studies. Diabetic Medicine, 30, 1026–1032.

    Article  CAS  Google Scholar 

  19. Allen, T., Zhang, F., Moodie, S. A., Clemens, L. E., Smith, A., Gregoire, F., Bell, A., Muscat, G. E., & Gustafson, T. A. (2006). Halofenate is a selective peroxisome proliferator–activated receptor γ modulator with antidiabetic activity. Diabetes, 55, 2523–2533.

    Article  CAS  Google Scholar 

  20. Nofziger, C., & Blazer-Yost, B. L. (2009). PPARγ agonists, modulation of ion transporters, and fluid retention. Journal of the American Society of Nephrology, 20, 2481–2483.

    Article  Google Scholar 

  21. Elasy, T. A., & Griffin, M. (2004). Thiazolidinedione use, fluid retention, and congestive heart failure: A consensus statement from the American Heart Association and American Diabetes Association: Response to Nesto. Diabetes Care, 27, 2096–2096.

    Article  Google Scholar 

  22. Cariou, B., Charbonnel, B., & Staels, B. (2012). Thiazolidinediones and PPARγ agonists: Time for a reassessment. Trends in Endocrinology & Metabolism, 23, 205–215.

    Article  CAS  Google Scholar 

  23. Zoete, V., Grosdidier, A., & Michielin, O. (2007). Peroxisome proliferator-activated receptor structures: Ligand specificity, molecular switch and interactions with regulators. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1771, 915–925.

    CAS  Google Scholar 

  24. Wright, M. B., Bortolini, M., Tadayyon, M., & Bopst, M. (2014). Minireview: Challenges and opportunities in development of PPAR agonists. Molecular Endocrinology, 28, 1756–1768.

    Article  Google Scholar 

  25. Step, S. E., Lim, H.-W., Marinis, J. M., Prokesch, A., Steger, D. J., You, S.-H., Won, K.-J., & Lazar, M. A. (2014). Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers. Genes & Development, 28, 1018–1028.

    Article  CAS  Google Scholar 

  26. Trujillo, M. E., & Scherer, P. E. (2006). Adipose tissue-derived factors: Impact on health and disease. Endocrine Reviews, 27, 762–778.

    Article  CAS  Google Scholar 

  27. Choi, J. H., Banks, A. S., Estall, J. L., Kajimura, S., Boström, P., Laznik, D., Ruas, J. L., Chalmers, M. J., Kamenecka, T. M., & Blüher, M. (2010). Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature, 466, 451.

    Article  CAS  Google Scholar 

  28. Sharma, A. M., & Staels, B. (2006). Peroxisome proliferator-activated receptor γ and adipose tissue—Understanding obesity-related changes in regulation of lipid and glucose metabolism. The Journal of Clinical Endocrinology & Metabolism, 92, 386–395.

    Article  Google Scholar 

  29. Marciano, D. P., Kuruvilla, D. S., Boregowda, S. V., Asteian, A., Hughes, T. S., Garcia-Ordonez, R., Corzo, C. A., Khan, T. M., Novick, S. J., & Park, H. (2015). Pharmacological repression of PPARγ promotes osteogenesis. Nature Communications, 6, 7443.

    Article  CAS  Google Scholar 

  30. Rizos, C., Elisaf, M., Mikhailidis, D., & Liberopoulos, E. (2009). How safe is the use of thiazolidinediones in clinical practice? Expert Opinion on Drug Safety, 8, 15–32.

    Article  CAS  Google Scholar 

  31. Nolte, R. T., Wisely, G. B., Westin, S., Cobb, J. E., Lambert, M. H., Kurokawa, R., Rosenfeld, M. G., Willson, T. M., Glass, C. K., & Milburn, M. V. (1998). Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature, 395, 137.

    Article  CAS  Google Scholar 

  32. Thangavel, N., Al Bratty, M., Akhtar Javed, S., Ahsan, W. and Alhazmi, H. A. (2017). Targeting peroxisome proliferator-activated receptors using thiazolidinediones: Strategy for design of novel antidiabetic drugs. International journal of medicinal chemistry, 2017.

  33. Bruning, J. B., Chalmers, M. J., Prasad, S., Busby, S. A., Kamenecka, T. M., He, Y., Nettles, K. W., & Griffin, P. R. (2007). Partial agonists activate PPARγ using a helix 12 independent mechanism. Structure, 15, 1258–1271.

    Article  CAS  Google Scholar 

  34. Capelli, D., Cerchia, C., Montanari, R., Loiodice, F., Tortorella, P., Laghezza, A., Cervoni, L., Pochetti, G. & Lavecchia, A. (2016). Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode. Scientific Reports, 6.

  35. Sheu, S.-H., Kaya, T., Waxman, D. J., & Vajda, S. (2005). Exploring the binding site structure of the PPARγ ligand-binding domain by computational solvent mapping†. Biochemistry, 44, 1193–1209.

    Article  CAS  Google Scholar 

  36. Farce, A., Renault, N., & Chavatte, P. (2009). Structural insight into PPARγ ligands binding. Current Medicinal Chemistry, 16, 1768–1789.

    Article  CAS  Google Scholar 

  37. Montanari, R., Saccoccia, F., Scotti, E., Crestani, M., Godio, C., Gilardi, F., Loiodice, F., Fracchiolla, G., Laghezza, A., Tortorella, P., Lavecchia, A., Novellino, E., Mazza, F., Aschi, M., & Pochetti, G. (2008). Crystal structure of the peroxisome proliferator-activated receptor γ (pparγ) ligand binding domain complexed with a novel partial agonist: A new region of the hydrophobic pocket could be exploited for drug design. Journal of Medicinal Chemistry, 51, 7768–7776.

    Article  CAS  Google Scholar 

  38. Thaggikuppe Krishnamurthy, P., JogheeNanjanChandrasekar, M., & JogheeNanjan, M. (2013). Newer approaches to the discovery of glitazones. Mini-Reviews in Organic Chemistry, 10, 66–72.

    Article  Google Scholar 

  39. Shang, Y., Hu, X., DiRenzo, J., Lazar, M. A., & Brown, M. (2000). Cofactor dynamics and sufficiency in estrogen receptor–regulated transcription. Cell, 103, 843–852.

    Article  CAS  Google Scholar 

  40. Smith, C. L., & O’malley, B. W. (2004). Coregulator function: A key to understanding tissue specificity of selective receptor modulators. Endocrine Reviews, 25, 45–71.

    Article  CAS  Google Scholar 

  41. Krishnamurthy Praveen, T., JogheeNanjanChandrasekar, M., & JogheeNanjan, M. (2013). Novel glitazones with diverse peroxisome proliferator activated receptor modulatory potential. Current Bioactive Compounds, 9, 221–234.

    Article  Google Scholar 

  42. Denizot, F., & Lang, R. (1986). Rapid colorimetric assay for cell growth and survival: Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. Journal of Immunological Methods, 89, 271–277.

    Article  CAS  Google Scholar 

  43. Zebisch, K., Voigt, V., Wabitsch, M., & Brandsch, M. (2012). Protocol for effective differentiation of 3T3-L1 cells to adipocytes. Analytical Biochemistry, 425, 88–90.

    Article  CAS  Google Scholar 

  44. Berger, J. P., Petro, A. E., Macnaul, K. L., Kelly, L. J., Zhang, B. B., Richards, K., Elbrecht, A., Johnson, B. A., Zhou, G., & Doebber, T. W. (2003). Distinct properties and advantages of a novel peroxisome proliferator-activated protein γ selective modulator. Molecular Endocrinology, 17, 662–676.

    Article  CAS  Google Scholar 

  45. Yi, W., Shi, J., Zhao, G., Zhou, X. E., Suino-Powell, K., Melcher, K., & Xu, H. E. (2017). Identification of a novel selective pparγ ligand with a unique binding mode and improved therapeutic profile in vitro. Scientific Reports, 7, 41487.

    Article  CAS  Google Scholar 

  46. Chen, Y., Ma, H., Zhu, D., Zhao, G., Wang, L., Fu, X. & Chen, W. (2017). Discovery of novel insulin sensitizers: Promising approaches and targets. PPAR Research, 2017.

  47. Pinaire, J. A., Miller, A. R., & Gregoire, F. M. (2008). Development of synthetic modulators of PPARs: Current challenges and future opportunities. PPAR Research, 2008, 7.

    Article  Google Scholar 

  48. Kubota, N., Terauchi, Y., Miki, H., Tamemoto, H., Yamauchi, T., Komeda, K., Satoh, S., Nakano, R., Ishii, C., & Sugiyama, T. (1999). PPARγ mediates high-fat diet–induced adipocyte hypertrophy and insulin resistance. Molecular cell, 4, 597–609.

    Article  CAS  Google Scholar 

  49. Chaudhary, S., Dube, A., Kothari, V., Sachan, N., & Upasani, C. D. (2012). NS-1: A novel partial peroxisome proliferator-activated receptor γ agonist to improve insulin sensitivity and metabolic profile. European Journal of Pharmacology, 684, 154–160.

    Article  CAS  Google Scholar 

  50. Oberfield, J. L., Collins, J. L., Holmes, C. P., Goreham, D. M., Cooper, J. P., Cobb, J. E., Lenhard, J. M., Hull-Ryde, E. A., Mohr, C. P., & Blanchard, S. G. (1999). A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation. Proceedings of the National Academy of Sciences, 96, 6102–6106.

    Article  CAS  Google Scholar 

  51. Sime, M., Allan, A. C., Chapman, P., Fieldhouse, C., Giblin, G. M., Healy, M. P., Lambert, M. H., Leesnitzer, L. M., Lewis, A., & Merrihew, R. V. (2011). Discovery of GSK1997132B a novel centrally penetrant benzimidazole PPARγ partial agonist. Bioorganic & Medicinal Chemistry Letters, 21, 5568–5572.

    Article  CAS  Google Scholar 

  52. Ebdrup, S., Pettersson, I., Rasmussen, H. B., Deussen, H.-J., Frost Jensen, A., Mortensen, S. B., Fleckner, J., Pridal, L., Nygaard, L., & Sauerberg, P. (2003). Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor α/γ agonist ragaglitazar. Journal of Medicinal Chemistry, 46, 1306–1317.

    Article  CAS  Google Scholar 

  53. Nagy, L., & Schwabe, J. W. (2004). Mechanism of the nuclear receptor molecular switch. Trends in Biochemical Sciences, 29, 317–324.

    Article  CAS  Google Scholar 

  54. Liu, C., Feng, T., Zhu, N., Liu, P., Han, X., Chen, M., Wang, X., Li, N., Li, Y., & Xu, Y. (2015). Identification of a novel selective agonist of PPARγ with no promotion of adipogenesis and less inhibition of osteoblastogenesis. Scientific Reports, 5, 9530.

    Article  CAS  Google Scholar 

  55. Burgermeister, E., Schnoebelen, A., Flament, A., Benz, Jr., Stihle, M., Gsell, B., Rufer, A., Ruf, A., Kuhn, B., & Märki, H. P. (2006). A novel partial agonist of peroxisome proliferator-activated receptor-γ (PPARγ) recruits PPARγ-coactivator-1α, prevents triglyceride accumulation, and potentiates insulin signaling in vitro. Molecular Endocrinology, 20, 809–830.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Science and Technology, Beijing Open University, A4 zaojunmiao, Haidian District, Beijing-100081, China

    Yunwei Li

  2. Department of Pharmacology, JSS College of Pharmacy (JSS Academy of Higher Education & Research), Mysuru, 570 015, Karnataka, India

    Nagashree KS

  3. Department of Pharmaceutical Chemistry, JSS College of Pharmacy (JSS Academy of Higher Education & Research), 20, Rocklands, Ooty, 643 001, The Nilgiris, Tamil Nadu, India

    Gowramma Byran

  4. Department of Pharmacology, JSS College of Pharmacy (JSS Academy of Higher Education & Research), 20, Rocklands, Ooty, 643 001, The Nilgiris, Tamil Nadu, India

    Praveen Thaggikuppe Krishnamurthy

Authors
  1. Yunwei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nagashree KS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gowramma Byran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Praveen Thaggikuppe Krishnamurthy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Praveen Thaggikuppe Krishnamurthy.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 445 KB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., KS, N., Byran, G. et al. Identification of Selective PPAR-γ Modulators by Combining Pharmacophore Modeling, Molecular Docking, and Adipogenesis Assay. Appl Biochem Biotechnol 195, 1014–1041 (2023). https://doi.org/10.1007/s12010-022-04190-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-022-04190-2

Keywords

Search

Navigation