Structure-Based Virtual Screening and Discovery of Novel Thiazole Derivatives as Potential PPARγ Modulators for Type 2 Diabetes Mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is a major metabolic disorder marked by insulin resistance and impaired β-cell function. Peroxisome proliferator-activated receptor gamma (PPARγ) serves as a key nuclear receptor regulating glucose and lipid metabolism. While thiazolidinedione (TZD) drugs effectively activate PPARγ, their clinical use is restricted due to adverse effects, highlighting the need for safer, selective modulators . Materials and Methods: An integrated in silico workflow was applied using the crystal structure of human PPARγ (PDB ID: 6ONJ). A virtual library of thiazole derivatives (SS-01 to SS-50) was screened through Lipinski’s rule, ADMET profiling, molecular docking, and density functional theory (DFT) analyses to predict binding affinity, pharmacokinetics, and toxicity. Results: Most compounds satisfied Lipinski’s criteria, exhibiting high predicted intestinal absorption (>85%) and balanced distribution properties. Docking studies identified several potent hits (SS-11 to SS-16) with strong binding affinities (−9.4 to −11.2 kcal/mol) and key hydrogen-bond interactions with Tyr473, His323, and Ser289. ADMET data indicated good oral bioavailability, moderate clearance, and low predicted toxicity, with minimal CYP inhibition and non-hepatotoxic profiles for top candidates. Discussion: The study revealed that selected thiazole derivatives display comparable or superior PPARγ binding relative to rosiglitazone, with improved safety profiles. Quantum chemical parameters supported their electronic suitability and receptor stability. Conclusion: This structure-based virtual screening identified novel thiazole-based scaffolds as promising PPARγ modulators with favorable pharmacokinetic and safety attributes, providing a strong foundation for synthesis and experimental validation as next-generation antidiabetic agents.