Tetrazoles as PPARγ ligands: A Structural and Computational Investigation

• DOI: 10.1101/2021.02.17.431624
• Publication Date: 2021-02-18T05:08:03Z
• Authors: Karina de Paula; Jademilson C. Santos; Ana Carolina Mafud; Alessandro S. Nas...
• Keywords: Rosiglitazone; Troglitazone; Tetrazole; Pioglitazone; Docking (animal); Thiazolidinedione

Abstract Diabetes is an important chronic disease affecting about 10% of the adult population in US and over 420 million people worldwide, resulting 1.6 deaths every year, according to World Health Organization. The most common type disease, 2 diabetes, can be pharmacologically managed using oral hypoglycemic agents or thiazolidinediones (TZDs), such as pioglitazone, which act by activating Peroxisome Proliferated-Activated Receptor γ. Despite their beneficial effects diabetes treatment, TZDs like rosiglitazone troglitazone were withdrawn due safety reasons, creating a void pharmacological options for treatment this disease. Here, we explored structure-based approach screening new chemical probes deeper investigation PPARγ activation. A class tetrazole compounds was identified named T1, T2 T3 purchased evaluated ability interact with ligand binding domain (LBD). binders micromolar range affinity, determined IC 50 values. Monte Carlo simulation compound revealed that ring makes favorable interaction polar arm receptor pocket. Finally, crystal structure PPARγ-LBD-T2 complex solved at 2.3 Å, confirming mode compound. also that, when helix H12 mispositioned, alternative conformation observed suggesting H12-dependent