Research Articles

Molecular Docking Studies of Novel Thiazolidinedionederivatives as PPARγ Modulators

Vol. 9 (2023) 12-21 Published October 4, 2026

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10.14805/jphchem.2023.art124

Abstract

Thiazolidinediones (TZDs), a well-known target of peroxisome proliferated receptors (PPARγ), have been clinically used as antidiabetic agents. PPARs belong to the nuclear receptor superfamily and are important targets (PPARs) for drugs that treat various metabolic disorders such as diabetes. We present comparative research on the meta-para substitution of benzylidene derivatives of thiazolidine-2,4-diones to identify their potential as modulators of PPARγ. PPARs are key drug targets in treating a range of metabolic disorders. In our previous study, we described 4-hydroxy benzylidene derivatives of thiazolidine-2,4-diones that exhibited a reversed orientation in the active site of PPARγ. The established pharmacophore was also discussed concerning the reversed conformation of the TZD fitting. In current silico studies, a focus is placed on meta-para-substituted benzylidene derivatives to identify H-bonding interactions analogous to those observed in the acidic head of rosiglitazone. All designed compounds exhibited strong hydrogen bonding interactions and displayed superior interaction energies compared to their monohydroxy counterparts. The results of a predicted ADMET report indicated that all molecules exhibited favourable hERG I & II properties, suggesting excellent metabolic stability.

References

  1. Scully, T. Diabetes in Numbers. Nature 2012, 485 (7398), S2–3. DOI: 10.1038/485s2a DOI: https://doi.org/10.1038/485S2a
  2. Darwish, K. M.; Salama, I.; Mostafa, S.; Gomaa, M. S.; Helal, M. A. Design, Synthesis, and Biological Evaluation of Novel Thiazolidinediones as PPARγ/FFAR1 Dual Agonists. Eur. J. Med. Chem. 2016, 109, 157–172. DOI: 10.1016/j.ejmech.2015.12.049 DOI: https://doi.org/10.1016/j.ejmech.2015.12.049
  3. Takada, I.; Makishima, M. Peroxisome Proliferator-Activated Receptor Agonists and Antagonists: A Patent Review (2014-Present). Expert Opin. Ther. Pat. 2020, 30 (1), 1–13. DOI: 10.1080/13543776.2020.1703952 DOI: https://doi.org/10.1080/13543776.2020.1703952
  4. Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.; Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.; Kliewer, S. A.; Lehmann, J. M. The Structure–Activity Relationship Between Peroxisome Proliferator-Activated Receptor γ Agonism and the Antihyperglycemic Activity of Thiazolidinediones. J. Med. Chem. 1996, 39 (3), 665–668. DOI: 10.1021/jm950395a DOI: https://doi.org/10.1021/jm950395a
  5. Horwitz, K. B.; Jackson, T. A.; Bain, D. L.; Richer, J. K.; Takimoto, G. S.; Tung, L. Nuclear Receptor coactivators and Corepressors. Mol. Endocrinol. 1996, 10 (10), 1167–1177. DOI: 10.1210/mend.10.10.9121485 DOI: https://doi.org/10.1210/mend.10.10.9121485
  6. Elbrecht, A.; Chen, Y.; Cullinan, C. A.; Hayes, N.; Leibowitz, Md; Moller, D. E.; Berger, J. Molecular Cloning, Expression and Characterization of Human Peroxisome Proliferator Activated Receptors γ1 and γ2. Biochem. Biophys. Res. Commun. 1996, 224 (2), 431–437. DOI: 10.1006/bbrc.1996.1044 DOI: https://doi.org/10.1006/bbrc.1996.1044
  7. Mukherjee, R.; Jow, L.; Croston, G. E.; Paterniti, J. R. Jr. Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-Activated Receptor (PPAR) Isoforms PPARgamma2 Versus PPARgamma1 and Activation with Retinoid X Receptor Agonists and Antagonists. J. Biol. Chem. 1997, 272 (12), 8071–8076. DOI: 10.1074/jbc.272.12.8071 DOI: https://doi.org/10.1074/jbc.272.12.8071
  8. Kota, B. P.; Huang, T. H.; Roufogalis, B. D. An Overview on Biological Mechanisms of PPARs. Pharmacol. Res. 2005, 51 (2), 85–94. DOI: 10.1016/j.phrs.2004.07.012 DOI: https://doi.org/10.1016/j.phrs.2004.07.012
  9. Marshall, P. G.; Vallance, D. K. Derivatives of Succinimide, Glutarimide, Thiazolidinedione and Methanol, and Some Miscellaneous Compounds. J. Pharm. Pharmacol. 2011, 6 (1), 740–746. DOI: 10.1111/j.2042-7158.1954.tb11011.x DOI: https://doi.org/10.1111/j.2042-7158.1954.tb11011.x
  10. Das, P. K.; Singh, G. B.; Debnath, P. K.; Acharya, S. B.; Dube, S. N. A Study of Anticonvulsant Activity of N-Substituted Derivatives of Succinimides, Thiazolidinediones and Their Structural Congeners. Indian J. Med. Res. 1975, 63 (2), 286–301. DOI: doi DOI: https://doi.org/10.1118/1.594198
  11. Sirotenko, A. A.; Ciavarri Jr., P. A. Some Hydrazones of 5-Phenyl-2,4-Thiazolidinedione. J. Med. Chem. 1966, 9 (4), 642–643. DOI: 10.1021/jm00322a061 DOI: https://doi.org/10.1021/jm00322a061
  12. Tawab, S. A.; Mustafa, A. A Comparative Study of Pharmacological and Toxicological Action of 2,4-Thiazolidinedione and Rhodanine and Its Derivatives. Arch. Int. Pharmacodyn. Ther. 1960, 128, 14–16. DOI: doi
  13. Hirschmann, R.; Dewey, R.; Schoenewaldt, E.; Joshua, H.; Paleveda Jr., W. J.; Schwam, H., et al. Synthesis of Peptides in Aqueous Medium. VII. Preparation and Use of 2, 5-Thiazolidinediones in Peptide Synthesis. J. Org. Chem. 1971, 36 (1), 49–59. DOI: DOI: https://doi.org/10.1021/jo00800a013
  14. Yasmin, S.; Jayaprakash, V. Thiazolidinediones and PPAR Orchestra as Antidiabetic Agents: From past to Present. Eur. J. Med. Chem. 2017, 126, 879–893. DOI: 10.1016/j.ejmech.2016.12.020 DOI: https://doi.org/10.1016/j.ejmech.2016.12.020
  15. Sohda, T.; Momose, Y.; Meguro, K.; Kawamatsu, Y.; Sugiyama, Y.; Ikeda, H. Studies on Antidiabetic Agents. Synthesis and Hypoglycemic Activity of 5-[4-(Pyridylalkoxy)Benzyl]-2,4-Thiazolidinediones. Arzneim. Forsch. 1990, 40 (1), 37–42. DOI: doi DOI: https://doi.org/10.1002/chin.199023199
  16. Parulkar, A. A.; Pendergrass, M. L.; Granda-Ayala, R.; Lee, T. R.; Fonseca, V. A. Nonhypoglycemic Effects of Thiazolidinediones. Ann. Intern. Med. 2001, 134 (1), 61–71. DOI: 10.7326/0003-4819-134-1-200101020-00014 DOI: https://doi.org/10.7326/0003-4819-134-1-200101020-00014
  17. Azoulay, L.; Yin, H.; Filion, K. B.; Assayag, J.; Majdan, A.; Pollak, M. N.; Suissa, S. The Use of Pioglitazone and the Risk of Bladder Cancer in People with type 2 Diabetes: Nested Case-Control Study. B.M.J. 2012, 344, e3645. DOI: 10.1136/bmj.e3645 DOI: https://doi.org/10.1136/bmj.e3645
  18. Nissen, S. E.; Wolski, K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N. Engl. J. Med. 2007, 356 (24), 2457–2471. DOI: 10.1056/NEJMoa072761 DOI: https://doi.org/10.1056/NEJMoa072761
  19. Fujita, T.; Sugiyama, Y.; Taketomi, S.; Sohda, T.; Kawamatsu, Y.; Iwatsuka, H.; Suzuoki, Z. Reduction of Insulin Resistance in Obese and/or Diabetic Animals by 5-[4-(1-Methylcyclohexylmethoxy) Benzyl]-Thiazolidine-2,4-Dione (ADD-3878, U-63,287, Ciglitazone), a New Antidiabetic Agent. Diabetes 1983, 32 (9), 804–810. DOI: 10.2337/diab.32.9.804 DOI: https://doi.org/10.2337/diabetes.32.9.804
  20. Pires, D. E.; Blundell, T. L.; Ascher, D. B. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J. Med. Chem. 2015, 58 (9), 4066–4072. DOI: 10.1021/acs.jmedchem.5b00104 DOI: https://doi.org/10.1021/acs.jmedchem.5b00104
  21. Laskowski, R. A.; Swindells, M. B. LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery. J. Chem. Inf. Model. 2011, 51 (10), 2778–2786. DOI: 10.1021/ci200227u DOI: https://doi.org/10.1021/ci200227u
  22. 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. Ligand Binding and coactivator Assembly of the Peroxisome Proliferator-Activated Receptor-Gamma. Nature 1998, 395 (6698), 137–143. DOI: 10.1038/25931 DOI: https://doi.org/10.1038/25931
  23. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv. Drug Deliv. Rev. 2012, 64, 4–17. DOI: DOI: https://doi.org/10.1016/j.addr.2012.09.019
  24. Jorgensen, W. L.; Duffy, E. M. Prediction of Drug Solubility from Structure. Adv. Drug Deliv. Rev. 2002, 54 (3), 355–366. DOI: 10.1016/s0169-409x(02)00008-x DOI: https://doi.org/10.1016/S0169-409X(02)00008-X
  25. Egan, W. J.; Zlokarnik, G.; Grootenhuis, P. D. In Silico Prediction of Drug Safety: Despite Progress There Is Abundant Room for Improvement. Drug Discov. Today Technol. 2004, 1 (4), 381–387. DOI: 10.1016/j.ddtec.2004.11.002 DOI: https://doi.org/10.1016/j.ddtec.2004.11.002

Author information

  • Deepak Shilkar

    Birla Institute of Technology

  • Sabina Yasmin

    King Khalid University,King Khalid University

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Shilkar, D.; Yasmin, S. Molecular Docking Studies of Novel Thiazolidinedionederivatives As PPARγ Modulators. J Pharm Chem 2023, 9, 12-21. https://doi.org/10.14805/jphchem.2023.art124.
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Received
November 14, 2021
Published
October 4, 2026
Updated
December 14, 2023
Section
Research Articles
Pages
12-21

Keywords

  • Drug Discovery
  • Thiazolidinedione
  • PPARγ Modulators
  • metabolic disorders

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