The Computer-Aided Drug Research Of AIDS Inhibitors

In recent years,with the development of science and technology,Computer-Aided Drug Design?CADD?has become a new kind of drug development technology.It is an interdisciplinary combining with chemistry,computer and statistics.The drug research methods using molecular simulation,computer software and graphics program to study the relationship between chemical structure and biological activity.And the structures of the known lead compounds were optimized to design and synthesize new drug molecules,in order to improve the biological activity of the drug.This paper using Three-Dimensional Quantitative Structure-Activity Relationship?3D-QSAR?and molecular docking technology as the main research method and supplemented by molecular design,the relationships between structures and activities were study by 3D-QSAR and the action modes between HIV-1 protease,HIV-1 non-nucleoside reverse transcriptase,HIV protease,neuraminidase inhibitors and enzymes were study by molecular docking,finally designed some new AIDS inhibitors.The main contents of this paper include the following five parts:1.In order to well understand the activities toward HIV protease inhibitor were governed by the chemical-biological interactions,QSAR models of 34cyclic-urea derivatives as HIV inhibitors were developed.The Quantitative Structure Activity Relationship?QSAR?model was built by using Comparative Molecular Similarity Indices Analysis?CoMSIA?technique.And the best CoMSIA model was Q_cv²?0.586?,R_cum²?0.931?for cross-validated and non-cross-validated,respectively.The predictive ability of CoMSIA model was further validated by the test set of 7 compounds,giving RPred2?0.973?.Docking studies were used to find the actual conformations of chemicals in active site of HIV protease,as well as the binding mode pattern to the binding site in protease enzyme.The information provided by 3D-QSAR model and molecular docking may lead to a better understanding of the structural requirements of 34 cyclic-urea derivatives and help to design potential anti-HIV protease molecules.2.The interaction of 5,6-dihydro-2-pyrone derivatives and HIV-1 protease was studied by molecular docking,and the relationship between the chemical structure of drug molecules and biological activity was studied by using Three-Dimensional Quantitative Structure-Activity Relationship?3D-QSAR?.Finally the obtained results of the models were multiple correlation coefficient(R_cum²)of 0.961,the cross-validated correlation coefficient(Q_cv²)of 0.897,the external validation correlation coefficient?Qext2?of 0.880,it can be seen that3D-QSAR model has a better predicted ability to anti-HIV activity of compound.3.The interaction between diaryl aniline derivatives and HIV-1 nonnucleoside reverse transcriptase was studied by using molecular docking,and the relationship between chemical structure of drug molecules and biological activity was studied by using the classic 3D-Holographic Atom Field Vector Method?3D-HoVAIF?and Multiple Linear Regression?MLR?method.The results of the model were multiple correlation coefficient?Rcum?of 0.949,the cross-validated correlation coefficient?Qcv?of 0.799,it was demonstrated that 3D-QSAR had a better predicted ability to anti-HIV drugs.4.In order to well understand the chemical-biological interactions governing their activities toward HIV-1 protease activity,a series of N-aryloxazolidinone-5-carboxamide derivatives?containing 38 compounds?as HIV-1 protease inhibitors was subjected to Three-Dimensional Holographic Atomic Vector Field?3D-HoVAIF?based 3D-Quantitative Structure Activity Relationship?3D-QSAR?analysis.Two different variable selection approaches that is Multiple Linear Regression?MLR?and Partial Least Squares?PLS?were employed for building the regression models.The best model obtained for MLR was the correlation coefficients(R_cum²)of 0.938,the cross-validated correlation coefficients(Q_cv²)of0.776,the correlation coefficients?Rtest2?of 0.811,the cross-validated correlation coefficients?Qext2?of 0.736,while the best PLS mode obtained was(R_cum²)of0.813,(Q_cv²)of 0.756,?Rtest2?of 0.936,respectively.Furthermore,docking studies was used to find the actual conformations of chemicals in active site of HIV-1 protease.It was found that compound activity and molecular docking results are basically consistent,and by further analysis it indicated that the compound 32 would form hydrogen bonding interactions with ILE50 and ASP29 of the protein receptor.5.In order to understand the activities of neuraminidase?NA?inhibitors were governed by chemical-biological interactions,the QSAR models of 28thiazolidine-4-carboxylic acid derivatives with inhibitory influenza A virus were developed.Here a Quantitative Structure Activity Relationship?QSAR?model was built by Three-Dimensional Holographic Atomic Vector Field?3D-HoVAIF?and Multiple Linear Regression?MLR?.The estimation stability and prediction ability of the model were strictly analyzed by both internal and external validations.The correlation coefficients(R_cum²)of established MLR model was0.984,the cross-validated correlation coefficients(Q_cv²)of MLR model was0.947,furthermore,the cross-validated correlation coefficients for the test set?Qext2?was 0.967,respectively.The binding mode between the compounds and the binding site of integrase enzyme was confirmed by docking studies.