The Study On The Mechanism And Virtual Screening Of HQC Inhibitors Against Alzheimer's Disease

Patients with Alzheimer's disease(AD)are characterized by the formation of high-molecular-weight amyloid-? protein(A?)in the brain,which interferes with neuronal function and causes neuronal cell death.Human glutaminyl cyclase(hQC)is mainly distributed in the hippocampus and hypothalamus of the brain and is responsible for the pyroglutamination(pGlu)of polypeptides.Glutamine cyclase is able to catalyze and enhance the formation of pGlu-A? polymer,which has significant cytotoxicity and pathogenicity.Therefore,specifically blocking the expression of hQC,reducing the formation of pGlu-A? and its neurotoxicity are of great significance for the prevention and treatment of AD.At present,the potential compounds acting on A? perform poorly in clinical trials,which is difficult for AD drug development.Therefore,the development of hQC inhibitors as a new entry point for AD treatment is urgent.In recent years,the studies of new hQC inhibitors have become a hot spot and frontier field in the current international anti-AD drugs research.Although some progress has been made in experimental research,the theoretical studies on the action mechanism between these compounds and receptor hQC are rare.Hence,on the basis of experimental results,the studies on the action mechanisms,virtual screening and molecular design of these compounds are very significant for the development of AD drugs.In this dissertation,molecular docking,three-dimensional quantitative structure-activity relationship(3D-QSAR)and molecular dynamics simulation methods were used to study the action mechanism of two recently reported series of compounds with good hQC inhibitories with anti-AD activities.3D-QSAR models with good predictive ability were established,and the appropriate binding modes of these compounds interacting with the receptor were also revealed.Based on these results,pharmacophore models were constructed and some novel and potential active hQC candidate inhibitors were obtained.This dissertation consists of the following five chapters:In the first chapter,we briefly describes the research status of Alzheimer's disease,the main pathological mechanisms,and the effects of hQC receptors on Alzheimer's disease.The structure characteristics and pathological mechanism of hQC,as well as the current status and the progress in the theoretical studies of hQC inhibitors are systematically summarized.In addition,the common methods and basic principles of computer-aided drug design and the significance of this study are also introduced.In the second chapter,3D-QSAR,molecular docking and molecular dynamics studies were performed on a series of imidazole-based hQC inhibitors.A 3D-QSAR model with good predictability was established and the main structural features affecting the activities were summarized.Two possible binding modes and conformations of these inhibitors interating with hQC receptor were revealed by docking analysis,and their differences were also discussed in detail.Molecular dynamics simulations validated the reliability of the docking results,and the binding energy calculations revealed the major factors affecting the binding to hQC receptor.Moreover,based on these results,some new compounds with higher activities have been reasonably designed.In the third chapter,a series of benzimidazole-based hQC inhibitors were selected to study the structure-activity relationship of these compounds and their interaction with hQC protein by 3D-QSAR,molecular docking and molecular dynamics simulation methods.A reasonable 3D-QSAR model was constructed and the main factors affecting the activities of the compounds were discussed.In molecular docking studies,the interaction patterns of different inhibitors and hQC protein were analyzed,and the comparisons of the differences of compounds in activities were also identified.Molecular dynamics simulations verified the correctness of the docking results and pointed out the key amino acids residues in the active pocket of hQC.Finally,based on the results obtained,some new compounds with more potent inhibitory activity were theoretical designed.In the fourth chapter,we analyzed the structure and activity information of hQC inhibitor molecules reported in the literature,and constructed a pharmacophore model based on the common features of ligands.The test set and decoy set compounds were used to verify the pharmacophore model to find the optimal one which is used to virtually screened the huge compound databases.And the preliminary screening compounds matching the best pharmacophore were obtained.The screened compounds were then subjected to molecular docking,pharmacokinetics,and toxicological screening and four preferred compounds were gained.Finally,the detailed binding modes,which are similar with the known hQC inhibitors,of these candidate compounds were determined by molecular dynamics simulations and binding free energy analysis.The four candidate compounds are potential hQC inhibitors and they are waiting for further experimental studies.In the fifth chapter,the whole work was summarized and prospect of this thesis was discussed.