Computer Aided Enzyme Inhibitor Molecular Design And Modeling Study

Computer aided drug design (CADD) is a new drug technology of research and development that based on multidisciplinary cross development of computer technology, molecular pharmacology and molecular biology, the speed of drug design and development was greatly accelerated for the application of CADD method in drug design. Two3D-QSAR methodologies and molecular docking were widely used in CADD and have been demonstrated to be successful. In our work, we used computer-aided drug design approach to study the activity of non-purine xanthine oxidase inhibitors, the inhibitory models of pyrazole derivatives as EGFR kinase inhibitors and the binding mechanism of C6-substituted phthalides with monoamine oxidases.This dissertation is composed of four chapters.Chapter1:A brief introduction of drug design was given. The quantitative structure-activity relationship (three-dimensional quantitative structure activity relationship,3D-QSAR) and molecular docking methods were described in detail.Chapter2:We made researches on relationship of non purine xanthine oxidase inhibitor structure and activity and the binding mode with its enzyme. In this work, we made a research on the non purine xanthine oxidase inhibitor. A model was established between the structure of the inhibitor and the activity through3D-QSAR, and then the factors that affected the activity of the inhibitor were studied and demonstrated by molecular docking. Finally, according to the obtained factors, we designed a series of molecules with higher predictive inhibitory activity through structure modification.Chapter3:Three dimensional quantitative structure-activity relationship (3D-QSAR) method was applied to forty-six EGFR kinase inhibitors. Through the analysis, we obtained the relationship between structure and activity and found out the key structure factors influencing the activity. According to the results, we designed several novel compounds with high predicted inhibition activity.Chapter4:We made binding analysis of phthalides and monoamine oxidase from some aspects including:AutoDock binding affinities of phthalide and C6-substituted phthalides into MAO-A and MAO-B; Correlation between binding free energy of docking and inhibitory bioactivity of MAO-A and MAO-B; Binding mode of several representative compounds in MAO-A active site and MAO-B active site via AUTODOCK4.2. Based on the binding mode information, we can revise the structure of the most active inhibitor in order to improve the inhibitory activity to monoamine oxidase and moreover we can make use of the docking method to research the binding mode of the new compound and predict the binding ability.