The Investigation On The Structural Dynamic Of The Interaction Between Amyloid Protein And Acetylcholine Receptor

With the increasing number of patients with vestibular disorders and Alzheimer's disease,tremendous pressure and triggered serious social problems of the current public health has been brought.In order to solve this problem,the detailed pharmacological mechanism,structural dynamic and the interactions between the drug molecule and target receptor molecules are necessary to be elucidated at the molecular level.The systematic exploration of the dynamic structural characteristics of pathogenic proteins and their interaction mechanisms with receptor molecules would lay the foundation for understanding the structural dynamic process of protein and the conformational effect to its function,as well as have important theoretical significance for us to understand the mechanism of disease and drug screening from the perspective of molecular structure.In this thesis,we aimed to reveal the interaction between two kinds of betahistine medicines and receptors,the A?_25-35 polypeptide fragment and the acetylcholine receptor.On this basis,the potential drug molecules were screened for the treatment of AD,and their pharmacodynamic assessments were also performed.The research contents are as follows:1.For the understanding of drugs'structural feature,two betahistine drugs'?betahistine hydrochloride and betahistine methanesulfonate?structures and vibrational spectra were calculated within DFT scheme and comparisons have been made with histamine.The drugs'interaction mechanisms with the receptors were revealed by using the molecular docking methods.The results show that the discrepancies of pharmacodynamic property would be resulted from minor molecular structure difference,and the vibrational spectra can be used for monitoring the drugs'metabolization.Generally,betahistine drugs have better performance in the docking patterns with receptors,like stronger interactions,forming more hydrogen bonds with receptors than histamine,and the betahistine methanesulfonate is found out to be the best for body recovery as it did in clinical presentation.2.The methodology established by the above-mentioned betahistine system was applied to the A?system to search the optimal binding conformation of A?_25-35 fragment interacting with acetylcholine receptor.Molecular dynamics simulation was also carried out to observe the structural kinetics of the docking complex and understand the interaction mechanism between ligands/receptors.The results from molecular docking and cluster analysis for molecular dynamic trajectory show that A?_25-35 and acetylcholine receptors would bound together in the ion channel of the acetylcholine receptor by intermolecular hydrogen bond and shape complementation,and these polypeptides in the docking complexes mainly present random coil structure and have a tendency to aggregate.The result of vibrational simulated spectrum obtained from the electrostatic frequency map indicates that the backbone amide-I band vibrational absorption peak of the A?polypeptide in the complexes locates at 1650.5 cm^-1,suggesting that the polypeptide mainly exhibits a random coil conformation,which is consistent with the results from cluster analysis.3.Further,six lead compounds which have interaction with?7-nAChRs receptor were obtained by virtual screening of multiple databases,and were also simulated by pharmacophores to construct eight new drugs.After that,their effects were evaluated by the analysis of blood-permeable brain barrier and molecular docking.Since these drugs have multiple hydrophobic groups,they exhibit high permeability to the blood-brain barrier and are highly affable with the?7-nAChRs receptor.So we think they can effectively inhibit the aggregation of A?_25-35 polypeptide in the ion channel and are two potential good drugs for the treatment of Alzheimer disease.4.The existing cleaning solutions of sample cell table in attenuated total reflection infrared spectrometer are often cumbersome and time-consuming.In view of the difficulty,a cleaning device was designed,which could simultaneously realize the automatic operation of detergent spraying and sample table cleaning,and efficiently complete the cleaning operation,freeing the hands of the experimenter.In the meantime,a device for adjusting the thickness of the liquid sample cell was designed to avoid the replacement of the sample cell.The combined use of some ratchets,differential cylinders,coarse adjustment knobs,fixed sleeves,and micrometer screws makes it possible to directly adjust the movement of the micrometer screw to push the sheet downward,which realize the quantitative adjustment and measurement of the thickness of the liquid sample cell.