Rational Drug Design Against β₃-AR And GLP-1R Related To Type â…¡ Diabetes Mellitus

Diabetes mellitus is the third vital disease following the cardiovascular disease and cancer, demonstrating serious threats to human health. The major cause of this disease is the relative or absolute insufficiency of insulin and the decrease of the glucose sensitivity to the islets. TypeⅡdiabetes mellitus (T2DM) is the most common form of diabetes, accounting for 90% of cases diabetes. However, the treatment of T2DM is still in the control stage rather than fundamentally cured; therefore, the discovery and design of novel antidiabetic drugs are significant.In chapter 1, the common methods and strategies of CADD have been reviewed.In chapter 2, we generated the pharmacophore model ofβ3-AR agonists on the basis of 35 training set compounds and the quality of the model was evaluated by predicting the activity of the test setting compounds and virtual screening. Meanwhile, the homology model ofβ3-AR was constructed based on the crystal structure ofβ2-AR. As the availability of the models ofβ1-,β2- andβ3-AR, molecular docking was carried out to detect the major contribution to the selectivity ofβ3-AR agonists. Besides, we superimposed the pharmacophore model onto the docking complexes for checking the alignment between the pharmacophore features and key residues, and the result further confirmed the reliability of our model.In chapter 3, the methods of homology modeling, molecular docking and molecular dynamics simulation were applied to obtain refined GLP-1R models, which provided start structures for further study. Meanwhile, normal model analysis and principle component analysis were performed to understand the detailed activation mechanism of the natural ligand GLP-1 to the receptor. Further more, virtual screening was carried out based on the average structures of Boc5/GLP-1R and Cpdl/GLP-IR extracted from the equilibrated stage of molecular dynamics. Finally, according to the docking score and the binding modes of the compounds to the receptor, some compounds were selected as final hits.The summary of the thesis is in the final chapter (chapter 4).