Studies On Design And Synthesis Of Dipeptidyl Peptidase â…£ Inhibitors

Objective:Glucagon-like peptide (GLP)-1is a kind of incretin hormone which can enhance the secretion of insulin and treat type2diabetes. Dipeptidyl peptidase â…£ is expressed as a glycoprotein on the surface of cells of most tissues. The active GLP-1can be converted to an inactive form by DPP-â…£. The inhibition of DPP-â…£ will increase the endogenous GLP-1which can reduce the glycosylated hemoglobin (HbAlc) levels in type2diabetics. In this research, we have docked several compounds with DPP-â…£ and synthesized some as DPP-â…£ inhibitors for anti-diabetic.Methods:First of all, two representative DPP-â…£ proteins (1x70and3bjm) and five DPP-â…£ inhibitors (NVP DPP728, LAF237, BMS-477118, GSK23A, MK-0431) in clinical trials have been choosed for molecule docking by Schrodinger Suite2007in this research. Secondly, according to the results of the molecule docking and the structures of the inhibitors above, we designed the compound frags and established a compound library. Thirdly, some designed compounds were synthesized and the anti-diabetic activities were evaluated.Results:Based on the molecule docking model of the DPP-IV inhibitors, we have found that the NH2in the compound structure is very important and the hydrophobicity groups in the both sides could enhance the bind between compound and protein. A libarary of fifty-six compounds, which fit the rules and well bound with protein, have been built. Eleven compounds were synthesized and five of them were detected to have the anti-diabetic activites. Conclusions:The virtual docking model of DPP-IV and the inhibitors were found. Accordingly, we built a libarary of fifty-six compounds which could bind with the protein very well. Eleven target compounds were synthesized and five of them were detected to have the anti-diabetic activites. The results of this research show that it is a practical way to design novel drugs on the basis of the structure of proteins.