Molecular Modeling And Drug Design On 5-HT_2CR And GLP-1R

Development of computer technique has brought the great development of theory and method of the computer aided drug design. As a subject dated to 20th century, computer-aided drug design was a comprehensive filed covering the knowledge of chemistry, biology, computer science, informatics and mathematics. With the improvement of computational chemistry and informational technique, there have existed more and more new computational methods. These methods shorten the duration of discovery of new medicines and decrease the manpower and financial sources of searching new medicines. Rational drug design makes the drug discovery purposive from blindness and accident.In Chapter 1, the basic knowledge of CADD was reviewed. Ligand-based method such as pharmacophore modeling and QSAR analysis, and receptor-based method like homology modeling and molecular docking were then introduced as important approaches used in the thesis.In Chapter 2, the pharmacophore model of 5-HT2cR antagonists was generated by HypoGen module of Catalyst. Features included in the pharmacophore are:one positive ionizable function (PI), one hydrogen-bond acceptor (HA), three hydrophobic points (HY). Enrich factor by virtual screening and regress analysis were used for the validation of the pharmacophore. Integrating the pharmacophore and the docking pose in the modeled 5-HT2cR structure, the mechanism between the 5-HT2cR antagonist and 5-HT2cR was studied. In order to optimize the ligand, a QSAR model was developed based on the docking pose of 5-HT2cR antagonist. These results were helpful for the discovery of 5-HT2cR antagonist and the treatment of neuropsychiatric disorders related to the hypo-function of central dopamine.In Chapter 3, the three dimensional structure of GLP-1 receptor with full length was generated with the bridge of GLP-1 (1DOR) on the basis of the extracellular crystal structure of GLP-1R (3IOL). Boc5, the small molecule agonist of GLP-1R, was docked into the modeled GLP-1R structure for the analysis of the interactions between GLP-IR agonist and GLP-1R. The key residues Trp39, Trp91 and Arg121 were well coincident to the experimental data. Our results would be helpful for the further design and discovery of small molecule GLP-1R agonists.Chapter 4 was the summary of the whole work.