Structures of PPARγ complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs

Abstract

Peroxisome proliferator-activator receptor (PPAR) γ is a nuclear hormone receptor that regulates glucose homeostasis, lipid metabolism, and adipocyte function. PPARγ is a target for thiazolidinedione (TZD) class of drugs which are widely used for the treatment of type 2 diabetes. Recently, lobeglitazone was developed as a highly effective TZD with reduced side effects by Chong Kun Dang Pharmaceuticals. To identify the structural determinants for the high potency of lobeglitazone as a PPARγ agonist, we determined the crystal structures of the PPARγ ligand binding domain (LBD) in complex with lobeglitazone and pioglitazone at 1.7 and 1.8 Å resolutions, respectively. Comparison of ligand-bound PPARγ structures revealed that the binding modes of TZDs are well conserved. The TZD head group forms hydrogen bonds with the polar residues in the AF-2 pocket and helix 12, stabilizing the active conformation of the LBD. The unique p-methoxyphenoxy group of lobeglitazone makes additional hydrophobic contacts with the Ω-pocket. Docking analysis using the structures of TZD-bound PPARγ suggested that lobeglitazone displays 12 times higher affinity to PPARγ compared to rosiglitazone and pioglitazone. This structural difference correlates with the enhanced affinity and the low effective dose of lobeglitazone compared to the other TZDs.

(<i>S</i>)-1,2,3,4-Tetrahydroisoquinoline Derivatives Substituted with an Acidic Group at the 6-Position as a Selective Peroxisome Proliferator-Activated Receptor γ Partial Agonist

“…Full agonists (compounds 1, 2, and 10) were also docked in the same manner for comparisons. The human PPARγ protein structures were derived from the Protein Data Bank (PDB; www.rcsb.org), 38) and 5Y2O (complexed with a full agonist) and 4A4V chain A (complexed with a partial agonist) were selected as the docking templates. Computational docking calculations were performed for both structures, followed by energy minimization to refine the docking pose.…”

A novel specific peroxisome proliferator‐activated receptor γ (PPARγ) modulator YR4‐42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet‐induced obese mice

“…Molecular simulation studies were performed using the Discovery Studio 2017 software package (BIOVIA, San Diego, California). The complex structure of PPARγ was obtained from the Protein Data Bank (code: 5Y2O) . The docking calculation was performed with CDocker protocol using default settings.…”

“…The complex structure of PPARγ was obtained from the Protein Data Bank (code: 5Y2O). 15 The docking calculation was performed with CDocker protocol using default settings. All calculations were carried out on a DELL Precision T5500 workstation.…”

Structural basis of altered potency and efficacy displayed by a major in vivo metabolite of the anti-diabetic PPARγ drug pioglitazone

“…structure of PPARγ LBD bound to PioOH at 1.88 Å resolution using molecular replacement ( Table 1). The X-ray crystal structure of Pio bound to PPARg LBD was recently solved at comparable resolution (1.801 Å; PDB code 5Y2O) (20). Both Pio and PioOH-bound PPARγ LBDs crystallized as dimers: h12 in chain A adopts an "active" conformation with the ligand bound in the orthosteric pocket, whereas h12 in chain B adopts an atypical conformation in which h12 docks onto adjacent molecules within the crystal lattice.…”

“…Full PPARγ agonists like the TZDs stabilize an active AF-2 surface conformation through a hydrogen bond network with residues near helix 12 including S289, H323, H449, and Y473 (20). Because Pio is known to have deleterious side effects such as weight gain and musculoskeletal complications, there is demand for a more sophisticated understanding of its effects on PPARγ structure and function (21).…”