Design, Synthesis, And Screening Of The Anti-obesity Compounds Based On The Three-Dimensional Structure Of Fatty Acid Synthase

Fatty acid synthase (FAS) is a new target of treating obesity, which is a key enzyme in the biosynthesizing of long-chain fatty acid. Mice given the FAS inhibitor-C75 demonstrated a profound decrease of food intake and body weight. It can decrease the risk of type II diabetes, cardiovascular and cerebrovascular diseases.The three-dimensional structure of KS domain of human fatty acid synthase(FAS) was modeled based on the structure of 1FJ8 protein of E. coli.. We docked the inhibitor molecular to the modeled protein, and gained the reasonable complex structure using the flexible docking method. Based the docking results, we have designed 8 class compounds, and have synthesized 83 compounds. The structures of these compounds have been identified by ¹H-NMR, ¹³C-NMR and MS methods. We have predicted the bioactivity of these compounds by the flexible docking method.The results of in vitro assay indicated that 26 compounds provided more strong inhibition than C75 to FAS at 60μmol. Then compound S8 had resulted in inhibition of the biosynthesizing of fatty acid. S8 can decrease the food intake, body weight, and NPY level on the hypothalamic of the BALBc and DIO mice in vivo, and it can also decrease the body fat, blood fat, blood glucose and insulin level of the DIO mice.The results of relationship between the structure and activities have indicated that the expecting bioactivities of compounds are similar to the experimental results. It indicates that the CADD methods can make the drug design more reasonable and efficient.