The hydrophobic tail of both Core A and Core C of agonists are buried well in the hydrophobic arm I and arm II that are formed by hydrophobic residues as shown by the green surface in Fig. 1 . Compared with GW409544 (shown with grey color in Fig. 1) , the compound of Comp#1 (purple color in Fig. 1 ) has more bulky molecular volume owing to the large hydrophobic Core C1, which is more fitted to the hydrophobic arm II, resulting in the much better binding affinity than GW409544 (cf. Table 1 ).