Design and in silico evaluation of Thiazole–Isoxazole hybrids as PPARγ-Targeted antidiabetic agents

Abstract

Introduction Diabetes mellitus is a chronic metabolic disorder characterised by persistent hyperglycemia resulting from impaired insulin secretion, action, or both. Prolonged hyperglycemia disrupts metabolic homeostasis and increases the risk of complications, including cardiovascular disease, neuropathy, nephropathy, and retinopathy. Current therapies target multiple pathways but are limited by reduced efficacy and adverse effects. Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and an important therapeutic target. Thiazole and isoxazole scaffolds possess antidiabetic potential, and their hybridisation may improve efficacy and safety. Objective To design and evaluate a novel series of thiazole-linked isoxazole derivatives targeting the alternate ligand-binding domain of PPARγ for potential antidiabetic activity. Result The designed compounds (C1–C210) were docked into PPARγ (Protein Data Bank: 5 GTN), yielding nine candidates with binding affinities of −11.11 to −9.97 kcal/mol. Reference ligands included pioglitazone, Q-35, and S-35, with C139 showing the highest affinity. Molecular dynamics simulations (200 ns) confirmed stability. Advanced Trajectory analyses indicate favourable conformational sampling, correlated residue motions, and a relatively confined conformational space. In silico drug-likeness profiling further supported their activity profile. Conclusion In this computational study, the thiazole-linked isoxazole compound C139 demonstrated probable antidiabetic activity against PPARγ. However, these findings remain predictive and require further validation through comprehensive in vitro and in vivo studies.