The familiar glitazone anti-diabetics are thiazolidinedione derivatives, known to elicit action through full agonistic activity on PPAR-γ receptors. Full agonists are known for the side effect of weight gain, while partial agonists are weak to non-adipogenic compounds possessing anti-diabetic property. This work identified a new synthetic oxadiazolyl thiazolidinedione (OXTZD) as a ligand for PPAR-γ receptor with partial agonist activity and less transactivation potential compared to rosiglitazone through in-vitro PPAR-γ competitive binding assay and PPAR-γ transactivation-based luciferase reporter assay, respectively. OXTZD did not induce significant lipid accumulation when compared to differentiation control which contained insulin in PPAR-γ-dependent adipogenesis assay. In-vivo studies have proved that OXTZD effectively reduced blood glucose level in type 2 diabetic rats and also improved glucose tolerance and insulin sensitivity. After 15 days of oral treatment with OXTZD, rats did not gain weight, suggesting that OXTZD was effective in suppressing the weight gain. Molecular docking of OXTZD to PPAR-γ, predicted hydrogen bonds with SER342, ARG288, and CYS285 residues in arm III of the ligand binding domain which are unique to the partial agonists. Results of in-vitro, in-vivo, and docking studies were in good correlation to the fact that OXTZD is a PPAR-γ partial agonist having glucose-lowering property and lacks the side effect of weight gain. In conclusion, OXTZD could be developed as a therapeutic agent for diabetes and/or serve as a lead compound for further drug design studies targeting PPAR-γ for effective management of type 2 diabetes without inducing weight gain.
Keywords: PPAR-γ partial agonist; Type 2 diabetes; docking; in-vitro; in-vivo; thiazolidinedione.
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