| The acquired immune deficiency syndrome (AIDS) which is induced by Human immunodeficiency virus (HIV) infection has become one of the major medical and humanitarian challenges. The HIV-1 Reverse transcriptase (RT)、 HIV-1 Protease (PR) and HIV-1 Integrase (IN), as important enzymes in the life cycle of HIV-1 virus, are important targets for the design of anti-AIDS drugs. In this paper, three-dimensional quantitative structure-activity relationships (3D-QSAR) study, molecular design and molecular docking have been performed by computer aided drug design (CADD), which provided theoretical basis for the development of anti-AIDS drugs.The dissertation includes five main parts as follows:1. Using Topomer CoMFA method, the relationships between dimensional structures and anti-HIV-1 activities of 41 HEPT inhibitors of HIV-1 Reverse transcriptase were studied, also, a good Topomer CoMFA model with preferable stability and prediction abilities was achieved. The multiple correlation coefficient of fitting r~2, cross validation q~2 and external validation qpred2 of the model are 0.983,0.859 and 0.945, respectively. Combining Topomer Search technology, the model was used to search R-groups with special activity contribution from ZINC database. Using sample 13 with the highest activity as the template, the R-groups selected were employed to alternately substitute for the corresponding R-groups of sample 13. As a result, we got a total of 20 compounds and their activities were further predicted by the Topomer CoMFA model, and 19 of them had higher activity than the template molecule. Finally, the inhibitors were docked into its targets HIV-1 RT using the method of molecular docking to analyze their binding modes.2. Using Topomer CoMFA method, the 3D-QSAR study of 60 2-amino-6-arylsulfonylbenzonitrile derivatives was established. The multiple correlation coefficient of fitting r~2, cross validation q~2 and external validation qpred2 of the model are 0.985,0.821 and 0.871, respectively. Combining Topomer Search technology,5 Ra and 2 Rb groups with special activity contribution were selected from ZINC database using the model.10 compounds were designed using the selected groups and their activities were further predicted by the Topomer CoMFA model, and 8 of them had higher activity than the template molecule. The results indicated that Topomer CoMFA model had both favorable estimation stability and good predictive capability. Topomer Search technology could be effectively used to screen and design new compound, and had good predictive capability to guide the design of new Anti-AIDS drugs.3. Using Topomer CoMFA method, the relationships between dimensional structures and anti-HIV-1 activities of 38 N-aryl-oxazolidinone-5-carboxamide derivatives were studied, also, a good Topomer CoMFA model with preferable stability and prediction abilities was achieved. The multiple correlation coefficient of fitting r~2, cross validation q~2 and external validation qpred2 of the model are 0.959,0.867 and 0.963, respectively. Combining Topomer Search technology, the model was used to search R-groups with special activity contribution from ZINC database.60 compounds were designed using the selected groups and their activities were further predicted by the Topomer CoMFA model, and all of them had higher activity than the template molecule. Finally, the binding modes between the inhibitors and its targets HIV-1 PR were studied using Surflex-dock. The results show that Asp25, Asp29, Asp30, Gly48 and Ile50 are critical residues for hydrogen bonding interaction.4.3D-QSAR studies for 60 non-peptide HIV-1 protease inhibitors were established using RASMS (Random Sampling Analysis on Molecular Surface) and Topomer CoMFA method, also, good models with preferable stability and prediction abilities were achieved. The multiple correlation coefficient of fitting r~2, cross validation q~2 and external validation qpred2 of the models are 0.936,0.803, 0.788 and 0.938,0.725,0.751, respectively. Combining Topomer Search technology, the Topomer CoMFA model was used to search R-groups with special activity contribution from ZINC database.20 compounds were designed using the selected groups and their activities were further predicted by the Topomer CoMFA model, and 18 of them had higher activity than the template molecule. Finally, the inhibitors were docked into its targets HIV-1 PR using the method of molecular docking to analyze their binding modes.5.3D-QSAR study for 62 carboxylic acid derivatives was established using Topomer CoMFA method. The multiple correlation coefficient of fitting r~2, cross validation q~2 and external validation qpred2 of the models are 0.942,0.870, and 0.766, respectively. The results indicated that the model had both favorable estimation stability and good predictive capability. Combining Topomer Search technology, the Topomer CoMFA model was used to search R-groups with special activity contribution from ZINC database.21 compounds were designed using the selected groups and their activities were further predicted by the Topomer CoMFA model, and 10 of them had higher activity than the template molecule. Finally, the binding modes between the inhibitors and its targets HIV-1 IN were studied using the method of molecular docking. |
PDF Full Text Request