Molecular Docking Studies of Novel Thiazolidinedionederivatives as PPARγ Modulators

Deepak Shilkar; Sabina Yasmin

doi:10.14805/jphchem.2023.art124

10.14805/jphchem.2023.art124

Keywords

Drug Discovery
Thiazolidinedione
PPARγ Modulators
metabolic disorders

How to Cite

(1)

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.

Funding data

University Grants Commission

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.

10.14805/jphchem.2023.art124

References

Scully, T. Diabetes in Numbers. Nature 2012, 485 (7398), S2–3. DOI: 10.1038/485s2a

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

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

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

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

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

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

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

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

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

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

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

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:

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

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

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

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

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

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

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

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

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

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:

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

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