Strongest predicted PPARγ binding for mulberrin and closest native-ligand contact pattern for moringin among six antidiabetic phytochemicals, with predicted cardiac and hepatic liabilities

Type 2 diabetes mellitus arises largely from insulin resistance and impaired glucose regulation, and PPARγ remains a central therapeutic target because it governs glucose and lipid metabolism and insulin sensitivity. Thiazolidinedione safety concerns have shifted interest to plant-derived partial or selective PPARγ ligands, yet few phytochemicals have been screened against PPARγ alongside a predicted pharmacokinetic and toxicity profile. This study evaluated artemetin, moringin, mulberrin, orientin, theaflavin, and tricin as potential PPARγ-targeted antidiabetic agents using molecular docking and ADMET (absorption, distribution, metabolism, excretion, toxicity) prediction. Docking used PPARγ (PDB ID: 1NYX) in AutoDock 4.2 with ragaglitazar as the co-crystallised native ligand and was accepted at a redocking RMSD below 2.0 Å; ADMET properties were predicted with pkCSM. Redocking gave an RMSD of 0.95 Å. Ragaglitazar showed -10.81 kcal/mol and the tested compounds ranged from -6.58 to -8.46 kcal/mol. Mulberrin showed the strongest predicted affinity (-8.46 kcal/mol), followed by orientin (-7.89 kcal/mol) and artemetin (-7.59 kcal/mol). Moringin shared the largest proportion of native-ligand contact residues (7 of 9; 77.8%). Artemetin showed the highest predicted human intestinal absorption (100%). Five of the six compounds were predicted to penetrate the blood-brain barrier poorly (log BB below -1), and none was predicted to be a renal OCT2 substrate. Moringin, orientin, and theaflavin were predicted to be neither CYP substrates nor inhibitors, whereas mulberrin and theaflavin were predicted to inhibit hERG II and moringin to be hepatotoxic. All compounds were predicted to be non-mutagenic. Experimental validation of PPARγ activity and of these safety signals is required.