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© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background

Obesity is a precursor for many co-morbid diseases. One of the main triggering factors for obesity is the abnormal expansion of white adipose tissue characterized by high rates of genesis and differentiation of precursor cells into mature adipocytes. As a result, targeting adipogenesis and adipogenic transcription factors opens new roadmaps for developing novel antiobesity pharmacotherapies. The present study was intended to rationally develop topiramate–phenolic acid conjugate for targeting obesity via inhibition of PPARγ which is often considered as the master regulator of adipogenesis.

Results

2D QSAR models were built to foretell PPARγ inhibitory activity of designed conjugates. The models presented excellent robustness, goodness of fit, and predictive capability compounds. The highest PPARγ inhibitory activity was predicted for T3 (topiramate–caffeic acid conjugate) with a pIC50 value of 7.08 µM. Molecular docking was performed for all the designed conjugates against PPARγ (PDB ID: 3VSO). The highest binding affinity was exhibited by T3 (− 11.27 kcal/mol) and displayed strong and stable interactions with the receptor within the allosteric pocket in comparison to the irreversible PPARγ antagonist, GW9662 (binding affinity, − 9.0 kcal/mol). These results were confirmed by subjecting the best-docked molecules to molecular dynamic simulations. The PPARγ–T3 complex was observed to be most stable with maximum number of hydrogen bonds (maximum observed RMSD = 0.57 Å at 100 ns) in comparison to PPARγ–topiramate and PPARγ–caffeic acid complexes. Consequently, T3 was synthesized and further subjected to in vitro screening. The TR-FRET assay established T3 as a PPARγ antagonist (IC50 = 6.78 µM). T3 also significantly reduced the lipid buildup in the 3T3-L1 adipocytes in a dose-dependent manner. In addition, T3 also reduced the protein expression levels of PPARγ as evidenced from western blot results.

Conclusions

Studies clearly indicated that T3 reduces adipose tissue cell differentiation by downstreaming PPARγ expression at protein levels, thereby emerging as a novel scaffold for antiobesity pharmacotherapy.

Details

Title
Design, synthesis, 2D-QSAR, molecular dynamic simulation, and biological evaluation of topiramate–phenolic acid conjugates as PPARγ inhibitors
Author
Padhy, Ipsa 1 ; Banerjee, Biswajit 1 ; Achary, P. Ganga Raju 2 ; Gupta, Pramodkumar P. 3 ; Sharma, Tripti 1   VIAFID ORCID Logo 

 Siksha ‘O’Anusandhan (Deemed to be University), Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Bhubaneswar, India (GRID:grid.484086.6) 
 Siksha ‘O’Anusandhan (Deemed to be University), Department of Chemistry, ITER, Bhubaneswar, India (GRID:grid.412612.2) (ISNI:0000 0004 1760 9349) 
 D Y Patil Deemed to be University, School of Biotechnology and Bioinformatics, Navi Mumbai, India (GRID:grid.412612.2) 
Pages
44
Publication year
2024
Publication date
Dec 2024
Publisher
Springer Nature B.V.
ISSN
23147245
e-ISSN
23147253
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2963240296
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.