In-silico Study of Molecular Docking and Dynamics Simulations for N-Substituted Thiazolidinones Derived from (R)-Carvone Targeting PPAR-γ Protein: Synthesis and Characterization

Abstract

In this article, we have selected the monoterpene (R)-carvone combined with thiazolidinone as scaffold. Moreover, this study details the synthesis, characterization, and theoretical analysis of novel (R)-Carvone-thiazolidinone-N-substituted derivatives, sourced from natural (R)-Carvone. The compounds were identified using HRMS, and 1H- and 13C-NMR spectral data. A theoretical analysis provided insights into the stability observed experimentally. The local electronic properties and topological features of two compounds 3 and d were studied using the Multiwfn tool and CrystalExplorer software. Specifically, the electron localization function, localized orbital locator and average local ionization energy were mapped to explore electron distribution, while interaction region indicator was used to analyze intermolecular interactions. An in silico docking study was conducted on the PPAR-γ protein to evaluate the binding affinity and interactions. Furthermore, a 200 ns molecular dynamics simulation was performed to confirm the stability of the compounds within the PPAR-γ protein’s binding site. The results indicated consistent stability for all three compounds under dynamic conditions. Lastly, in silico evaluations of drug-likeness and toxicity prediction showed that all compounds adhere to the criteria of both Lipinski’s Rule of Five and Jorgensen’s Rule of Three, confirming their potential as drug candidates.