The Research Of Some Carbohydrate Binding Protein And Ser/Thr Protein Phosphatase Using Computer Aided Drug Design Method

This paper uses Computer Aided Drug Design (CADD) method to research the mechanism between Carbohydrate Binding Proteins(CBP) and their ligands. Using the molecular Docking method to predict the way heparin binding to Hiv-1 envelope protein gp120 and giving the key'amino acids in the interaction . And also evaluating two docking software in the capability of predicting the Carbohydrate Recognize Domain(CRD) on the CBP , which gives a cheap solution to research the CBP with known structure and unknown structure and unknown capability. Then ,this paper discovers the Ser/Thr Protein Phosphatase inhibitor Catharidin and its analogs and give direction to modify them. Also analyzing the Ser/Thr Protein Phosphatase 2A (PP2A) selective inhibitor -Fostriecin , finding the key field on the PP2A and giving some information in developing new inhibitor with selectivity. At last, the 3D-QSAR of Capsaicin, a new kind of compond with analgetic activity was studied .Without the receptor structure , a credible model is built by Compare molecular Field Analysis (CoMFA) method to guide the modification of the Capsaicin analogs.This paper has 3 Parts and 7 Chapters:Part 1: Research on CBPChapter 1: This chapter is the background knowledge of chapter 2 and 3. It summers the development of the Carbobiology , introduces the CADD method using in the CBP research and some successful example. Some information of Lectin and Heparin binding protein , two important kinds of CBP , concluded in this chapter.Chapter 2: Docking method is used to find the way heparin binding to Hiv-1 envelope protein gp120 to get the detail of interaction. In this chapter, first , thedocking method is used on bFGF .which is an important Factor interacting with heparin , to make sure the capability . Then the Insight II software package is used to build the gp120 model and monosacchride ,disaccharide and trisacchride used as probe molecules rolling over the surface of the protein .After the statistics , the best binding site isdiscovered in all of the results and a hexsacchride is docked to it.Chapter 3: The capability on predicting the CRD of two docking software : GRID/GROUP and AutoDock ,which can make global search around the protein ,is evaluated in this chapter. By comparing the X-ray crystal structure with the docking results , the conclusion is made that these two softwares can be good tools to research the protein with CRD despite some shortcoming in them. The a kind of lectin , Con A, which is often used as tool protein was analyzed using one of the software. With the help of a binding site analyzing software ,CASTp, some new information is found.Part 2: Research on Ser/Thr Protein Phosphatase (PP) and inhibitorsChapter 4 : This chapter is the background knowledge of chapter 5 and 6. The biological function of PP and the inhibitor discovery history are introduced . According to the structure of PP, a common binding model of inhibitors is concluded.Chapter 5 : The flexible docking method is used to discover the binding method of PP1 inhibitor -Catharidin , and also Catharidin and Catharidic acid analogs which were synthesized by our group are docked to PPL With the help of a direct molecule design software, GRID, which uses atoms as probe to scan the binding filed, the best binding mode to its inhibitors of PP1 is found, more structure modification information is shown .Chapter6 : This Chapter shows the detail of how to analyze PP2A, a subtype of PP , selective inhibitor - Fostriecin .The docking and atom probing method are used to discover the unique interaction mode of Fostriecin .The CADD method tells more about how to design a selective PP inhibitor.Part 2: Research on CapsaicinChapter 7: Capsaicin is a kind of lead compond which has regulating activity on afferent nerve cell. Some experiment has prove that Capsaicin can interact with the receptor or ion channel on the membrane ,while the accurate molecular mechanism is still unknown. Using the Compare molecular Field Analyses method , a computer model is built u...