The Studies On Drug Molecular Design For Related Targets Of Acetylcholine

The studies of the drug from the receptor point, have already obtained the very high theoretical support, and accompanied the birth of the relevant application. For example, Sybyl-X2.0 software, Gaussian software and Gromacs dynamics software. This thesis consists of five chapters, the first chapter is an overview, the second chapter is based on the study of acetylcholine receptor, the third 、 fourth and fifth chapters are based on the study of acetylcholinesterase.The first chapter is Alzheimer’s disease with its ligand and target for overview: Since the AD was discovered, many hypothesis have been proposed and verified in the clinically, the most famous hypothesis was cholinergic hypothesis which the AD patients’ brain acetylcholine level was decline, accordingly, the ACh E target had been fully studied. Further,for the study of the AD, it was found that AD had the multifactorial and complex etiology, and had many targets including in this disease, so a so-called “single entity-multitarget ligand” approaches study had prompted and opened up a new path with this paradigm for the optimal AD disease treatment compound.The second chapter is based on acetylcholine receptor target’s antiasthmatic drug molecular docking and design research: According to the reports in document, fritillaria contains main alkaloids and have antiasthmatic effect. The studies on antiasthmatic mechanism mainly concentrates in the antagonism of M acetylcholine receptor. The chapter takes peimisine as ligand and acetylcholine receptor（M3） for docking with the Surflex-Dock method, and carries on the analysis. The last, according to the docking analysis results to design some compounds for docking again, in order to find new antiasthmatic drugs. The study on the acetylcholine receptor（M3） targets and provides a theoretical basis about the development of fritillaria for cough and asthma drug.The third chapter is the studies on heterodimers of Donepezil and Huperzine A as novel acetylcholinesterase inhibitors: This chapter mainly study an important target of AD, analysis and design excelletnt acetylcholinesterase inhibitors, so as to achieve the purpose of treating Alzheimer’s disease. Through pharmacophore modeling, molecular docking, molecular superposition, studying hybrid of Donepezil and Huperzine A, and the compounds S-17 b, R-17 b of the total electron density（electrostatic potential） was studied. And through the pharmacophore modeling and molecular docking virtual screening some excellent compound. Finally, according to the screening of compound and S₁7b compound carry on partial combination, the design of the 16 molecules, according to the docking parameters（Total_Score, Consensus Score）, finding S₁7bc3 compound has the same characteristics as S₁7b compound, so it can be used as a novel lead compound, for continuing design and research. And on the basis of molecule S-17bc3 to further design 9 molecules that is S₁7bc31-S₁7bc39.The forth chapter is from structure-activity relationship and conformational restriction approach analysis drug molecular of AD, and the design of dual site dual target drug molecular: Research and development therapeutic AD disease drug of dual site multiple targets has a broad application prospect. Therefore, some molecules are designed according to ACh E dual sites inhibitors, BACE-1 inhibitors center framework, molecular docking, QSAR prediction. Finally, a dual sites inhibitory and the dual targets inhibitory molecule（E2） has been designed, and it has a certain effect on the treatment of AD disease, and 6 molecules（F1-F6） have also designed from E2 molecule stucture.The fifth chapter mainly use dynamics method for simulation analysis of ACh E protein, then use the surflex-dock method, docking to get the receptor-ligand complexes. In this chapter, on the basis of the surflex-dock docking, it was found that the molecular conformation of S₁7b had small changes and lower binding energy after dynamics simulation; The ACh E-S₁7b and ACh E- R₁7b complexes system also carried on dynamics simulation, and found that the S₁7b and donepezil had similar results. From the analysis of RMSD and RMSF change curves, the inhibitory potency of S₁7b was a little better than donepezil. The important residues of active site had smaller RMSF fluctuating value, which suggests that the important residues would be rigid structure, and not easy to influence by ligand. The result provides feasibility and rationality for using conformational restriction approach to design molecules. So this chapter combined molecular docking and conformational restriction approach to design S₁7bc310 from the point of view of the ligand S₁7b molecule, and has explained why the designed molecules in the third chapter had the different conformation（such as flip） in the active pockets.