Because the natural ligands of PPARs are fatty acids, the binding site of PPARs is almost hydrophobic. Several hydrophobic interactions with three arms of the Y-shaped ligand binding to the site are taken as the key point for designing the new PPARs agonist [49] . The PPAR binding site is composed of three arms, namely Arm I, Arm II, and Arm III, as explicitly marked in Fig. 1 . The first arm has mainly polar character including the AF2 (transcriptional activation function 2) helix indicated by red ribbon. The hydrophilic head group of the PPAR ligands forms a network of hydrogen bonds with AF2 of Arm-I; while the hydrophobic tail of PPAR agonist is either interacts with Arm II or Arm III. The network hydrogen bonds forms an important conformation for AF2-helix to generate a charge clamp, thus reducing the mobility of AF2 via binding a ligand and hence make it able to regulate the gene expression [4] . The drug-like database and the fragment database derived from ZINC [50] were used for virtual screening and core hopping searching, respectively.