QSAR Study Of Anti-HIV And HCV Drugs

AIDS,which was produced by human immunodeficiency virus,and hepatitis C,which was caused by hepatitis C virus?HCV?infection all are viral epidemic in the world today.They do great harm to people's health,but there is no effective medicine to treat it,so it becomes one of the major problems in medical research.As an important target protease in the lifecycle of the virus,HIV-1 Reverse Transcriptase?RT?,HIV-1 Integrase?IN?,HCV NS5B polymerase are the key to our study of anti-AIDS,hepatitis C drugs.In this paper,different inhibitors were studied by quantitative structure-activity relationship?QSAR?,molecular project and molecular docking,which offered academic for designing high activities drugs.The research of this paper includes as follows:1.The 3D-QSAR models were developed from a data set of 21thiazolidenebenzenesulfonamide derivatives by using Topomer CoMFA method.The best Topomer CoMFA model had a cross-validation q²value of 0.964,a non cross-validation r²value of 0.801 and an external validation statistic Q²_extxt value of 0.959.The study also used the methodology of fragment-based drug design to virtual screen new moleculars by using Topomer Search technology.The obtained 3 Ra groups and 7 Rb groups with the highest contribution values were searched from ZINC database,and 21 new moleculars with effective high activities were designed.It is demonstrated that Topomer CoMFA model had good stability and predictive ability.Topomer Search technology could be effectively used to screen and design new compound,which provided the basis for the design of new anti-AIDS drugs.2.A 3D-QSAR model was conducted on 72 HIV-1 NNRTIs using Topomer CoMFA.The best Topomer CoMFA model had a cross-validation q²value of 0.899,a non cross-validation r²value of 0.7888 and an external validation statistic Q²_extvalue of 0.942.The results indicated that the model had well stability and favourable predictability at the same time.Topomer Search was used to search appropriate R groups from ZINC database,14 new compounds were designed thereby.These results strongly suggest that the Topomer Search is effective in screening and can be a useful guide in the design of new HIV-1 drugs.Ligands of the template molecule and new designed compounds were used for molecular docking to study the interaction of these compounds with the protein receptor.The results show that the ligands would form hydrogen-bonding interactions with the residues Ala28,Asp 29,Gly49 and Ile50 of the protein receptor generally,thereby providing additional insights for the designing of even more effective drugs.3.A 3D-QSAR model was conducted on 53 HIV-1 integrase inhibitors?IN?using Topomer CoMFA.The best Topomer CoMFA model had a cross-validation q²value of 0.930,a non cross-validation r²value of 0.726 and an external validation statistic Q²_extvalue of 0.855.The results of this model illstrated that it had well stability and favourable predictability at the same time.Topomer Search was used to search appropriate R groups from ZINC database,28 new compounds were designed thereby.Ligands of the template molecule and new designed compounds were used for molecular docking to study the interaction of these compounds with the protein receptor.The results show that the ligands would form hydrogen-bonding interactions with the residues LEU58,THR83,GLN62,MET155,LYS119 and ALA154 of the protein receptor generally,thereby providing additional insights for the designing of even more effective anti-HIV drugs.4.The 3D-QSAR model of 48 HCV NS5B polymerase inhibitors had been constructed using Topomer CoMFA.The best Topomer CoMFA model had a cross-validation q²value of 0.957,a non cross-validation r²value of 0.739 and an external validation statistic Q²_extvalue of 0.963.The results indicated that the model had well stability and favourable predictability at the same time.Topomer Search was used to search appropriate R groups from ZINC database,14 new compounds were designed thereby.Ligands of the template molecule and new designed compounds were used for molecular docking to study the interaction of these compounds with the protein receptor.The results show that the ligands would form hydrogen-bonding interactions with the residues GLN446,ILE447,TYR448 and GLY449 of the protein receptor generally,thereby providing additional insights for the designing of even more effective anti-HCV drugs.