Identification of novel multitargeted PPARa/?/d pan agonists by core hopping of rosiglitazone

Wang, Xue-Jiao; Zhang, Jun; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

Identifying PPARα/γ/δ pan agonists by core hopping of rosiglitazone interaction. 32, 33 The Linear Constraint Solver algorithm was used for all of the bond restriction. [34] [35] [36] Results and discussion Ligand binding domains of the PPAR receptors The X-ray crystallography studies showed that the ligand binding domain of the PPARs was composed of 12α-helix and 4 antiparalleled β-sheet. The three subtypes of PPARs were 60%-70% sequence similarities with RMSD between Cα atoms 1 Å. In addition, the ligand binding domain of the PPARα/γ/δ formed a Y-shaped hydrophobic pocket with a volume of about 1,300 Å 3 . The AF-2 region of H12 helix played an important role in the process of the activation of PPARs. As for PPARδ, the AF-2 region was significantly narrower, which was not suitable for binding ligands with a larger polar head. 37 core hopping and docking A total of 42,000 compounds were obtained by core hopping of rosiglitazone. These compounds were docked into PPARα (pdb 1I7G), PPARγ (pdb 2PRG), and PPARδ (pdb 2ZNP), respectively, screening out 23 compounds with higher docking scores and better binding poses than the original ligands. Further ADMET prediction studies produced the top eight compounds ( Table 1 ). The docking scores of these compounds with PPARα and PPARγ were higher than the original ligand AZ242 and rosiglitazone, respectively. The docking scores of these compounds with PPARδ were somewhat lower than the original ligand TIPP204. In addition, the hydrogen bond distances between compounds and PPARs were 3.20 Å, 38, 39 and the values were equal to the original ligand.