Vol. 7, Issue 2, Part A (2025)

Type 2 diabetes mellitus (T2DM) remains a major global health challenge, characterized by insulin resistance and impaired glucose homeostasis. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have demonstrated therapeutic potential in improving insulin sensitivity and glycemic control. However, currently available PPARγ agonists often exhibit undesirable side effects, necessitating the search for safer and more effective alternatives. In this study, molecular docking approaches were employed to evaluate the binding interactions and affinities of novel piperazine-derived compounds as potential PPARγ agonists. Ligand structures were designed and energy-minimized prior to docking using advanced computational tools. The crystal structure of PPARγ was obtained from the Protein Data Bank and prepared for docking simulations. Docking results revealed that the piperazine scaffold exhibited favorable interactions with critical residues in the ligand-binding domain of PPARγ, including hydrogen bonding and hydrophobic contacts essential for receptor activation. Several derivatives demonstrated higher predicted binding affinities compared to known reference agonists, suggesting improved efficacy. In addition, ADMET predictions indicated acceptable pharmacokinetic profiles and reduced toxicity risks. These findings highlight the potential of piperazine-derived compounds as optimized PPARγ agonists for antidiabetic therapy. Further in vitro and in vivo studies are recommended to validate their biological activity and develop them as promising candidates for T2DM treatment.