| Research backgroundWith the developing society, more and more people become diabetic, especially for the young people. Diabetes is tremendously harmful to human society because hyperglycemia can cause serious complications such as cardiovascular disease,kidney failure, blindness, amputation and so on. 95% of all diabetic patients are type2 diabetes, therefore, type 2 diabetes has become the main direction of diabetes research. The main pathogeny of type 2 diabetes is the insulin resistance of skeletal muscle, adipose and liver tissue which will lead to disturbance of carbohydrate metabolism and other diseases caused by hyperglycemia. PPAR gamma protein is an important target in the research of insulin resistance. The activation of PPAR gamma induces transcription and translation of proteins which plays different roles in regulation of the metabolism of living matter. CAP is generated by the PPAR regulation, which not only can promote the transportion of extracellular glucose into the cell, but also improve the applicated efficiency of insulin. But the drugs of PPAR gamma agonist are less in the drug market, and have serious side effect. Therefore,the research and development of novel drugs of PPAR gamma agonist become very pressing.Objective1, Design novel leading compounds of PPAR agonist using computer aided drug design method.2, Analysis and synthesize the leading compounds of PPAR gamma agonist.3, Study on the anti-diabetic activity of the leading compound of PPAR gamma agonists.Method1, Search the chembl and drugbank database for the leading compounds of PPAR gamma agonist according to the PPAR gamma protein structure of 4EMA and2 XKW and using Libdock, CDOCKER and Surflex-Dock docking methods in Discovery Studio3.0 and sybylX-2.0 software. 2, the use of MD to verify the results3, the synthetic PPAR agonists lead compounds4, Create type 2 diabetes models of SD rats by using the method of feeding with high sugar diet and induced by STZ.5, Intragastric administration of the leading compounds in type 2 diabetic rats,determine the physiological index and hormone levels of blood serum, liver,pancreas, skeletal muscle, adipose tissue, and observe the pathological changes of liver and pancreas.6, Create insulin resistant model of 3T3-L1 cells.7, Measure the changes of 3T3-L1 cell glucose tolerance after leading compound effects on insulin resistance model.8, Measure the expression of PPAR gamma protein in serum, liver, skeletal muscle,adipose tissue.Result1, Lead compound 794 ap with the higher docking score was obtained by using virtual screening method.2, Synthesis the lead compound 794 ap and used in the bioactivity assay.3, The successful rate of creating type 2 diabetes models was 70%.4, when the drug concentration was 3mg/mL, the blood glucose is obviously lower,and the glucose tolerance of type 2 diabetic rat is good.5, 794 ap compound can reduce the contents of TCH and TG in the serum and liver homogenate, expecially when the drug concentration was 5mg/mL.6, 794 ap compound can reduce the contents of FFA and INS in the serum, expecially when the drug concentration was 1mg/mL.7, 794 ap compound can improve the pathology phenomenon of liver and pancreas organ.8, 794 ap compounds can improve glucose consumption in the insulin resistant cells of 3T3-L1 cell, and 1.5nmol/L is the most optimum concentration for treatment.9, The expression of PPAR gamma protein were different in different tissues, when the 794 ap compound concentration was 5mg/mL, the expression of PPAR gamma protein improved significantly.ConclusionAll the result proved that leading compounds have anti-diabetic activities, but the most optimal concentration of the leading compounds was not constant. The reason for the phenomenon may be caused by the individual differences of animal orthe inconsistent injury of pancreatic islet. But, from all the experimental data, the concentraition of 5, 7mg/mL can be identified as the best optimal drug concentration. |
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