Rational design, molecular docking, dynamic simulation, synthesis, PPAR- competitive binding and transcription analysis of novel glitazones

Over the last decade, peroxisome proliferator-activated receptor (PPAR-gamma) has emerged as one of the important therapeutic targets in several metabolic and neurodegenerative disorders. The remarkable progress in drug discovery has resulted in designing novel PPAR-gamma activators. Thiazolidinediones, also known as glitazones, have been demonstrated to play a significant role in treating several neurodegenerative diseases, diabetes, and cancer. Despite its wide range of adverse effects, glitazones orchestrate significant pharmacological activities. In this backdrop, we designed and synthesised novel glitazones for potential PPAR-gamma binding activity. The synthesised novel compounds were structurally analysed using H-1 NMR, C-13 NMR and FT-IR. The interaction binding modes, binding free energy, and crucial amino acids involved in interactions of designed compounds with the target protein were studied using molecular docking. Further, molecular dynamic modeling was used to evaluate the stability of the best-docked complexes. TR-FRET, an in vitro PPAR-gamma competitive binding assay, was performed to confirm the affinity of the well-docked compounds for the target protein. It demonstrated that the compounds explicitly bind to the PPAR-gamma ligand-binding domain to exhibit pharmacological activity. The cytotoxicity of synthesised compounds was performed and confirmed the PPAR-gamma transcription activity on SH-SY5Y cell lines (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

Peroxisome proliferator-activated receptor (PPAR-gamma) has become an important therapeutic target in various metabolic and neurodegenerative disorders. This study focuses on designing novel glitazones and evaluating their pharmacological activities through structural analysis, docking, and in vitro experiments.