QSAR And Molecular Docking Studies On HIV-1 NNRTIs

Acquired immunodeficiency syndrome?AIDS?is a fatal disease caused by human immunodeficiency virus?HIV?.HIV can be divided into type I?HIV-1?and type II?HIV-2?,and there is a certain immune cross-reaction between the two.It is reported that HIV-1 is one of the most easily transmitted and infected viruses in humans,so the vast majority of AIDS is caused by HIV-1.Reverse transcriptase?RT?plays a key role in the replication cycle of HIV-1.Therefore,HIV-1 reverse transcriptase has always been a major biological target in the development of anti-AIDS drugs.In this paper,Topomer comparative molecular field analysis?Topomer CoMFA?was used as the main 3D-Quantitative structure activity relationship?3D-QSAR?research method to study five NNRTI systems of S-alkoxybenzylpyrimidinedione derivatives,thionocarbamates derivatives,diarylpyrimidine derivatives,1,3,4-thiazolidinone derivatives and diaryltriazines.1.Topomer CoMFA was used to build a 3D-QSAR model for 216-napthylmethyl substituted S-DABO analogues in this paper,with key parameters as follows:N=3,q²=0.659,r²=0.917,F=44.418,SEE=0.222,q²_stderr=0.45,r²_stderr=0.22,respectively.The results show that the model was better.Topomer search was employed to select R group in ZINC molecular database.As a result,a total of 8 new compounds with better activity than template molecules were designed.Then,we explored that interaction mode between the new compounds and the HIV-1 reverse transcriptase acceptor using Surflex-dock.The results suggest that the new compounds obviously with LYS101?LYS103?TYR318 sites of HIV-1 reverse transcriptase.2.Thiocarbamate?TCS?has been identified as a new non-nucleoside HIV-1reverse transcriptase inhibitor.The 3D-QSAR of TCS inhibitors was studied in this paper.The R-group search technique was used in the Topomer CoMFA method.The three-dimensional quantitative structure-activity relationship analysis of 111 thiocarbamate derivatives was carried out.The results showed that the q² and r² of the 3D-QSAR model were 0.616 and 0.751,respectively.In experiment 2,the first 60 molecules were analyzed and the results showed that q²and r² were 0.777 and 0.913,respectively.The results of two experiments show that the model has good stability and prediction ability in statistics,but in contrast,experiment 2 is more favorable to the design of anti-AIDS drugs.3.The diarylpyrimidine?DAPY?compounds are important in the nonnucleoside reverse enzyme inhibitors.The present study aims to study the three-dimensional quantitative structure-activity relationship?3D-QSAR?of DAPY inhibitors and their binding mode.We build a 3D-QSAR model involving24 training DAPY inhibitors based on Topomer CoMFA,and 8 molecules are employed to validate the external predictive power of the model obtained.The r²,q² and Q² _extof the model were 0.979,0.597 and 0.756,respectively.Topomer Search was employed as a tool for virtual screening in drug-like compounds of ZINC database?2012?.Finally,we successfully design 30 new molecules with higher activity than that of all training and test inhibitors.The results show that the model was better.Topomer Search technique can be used to screen and design new compounds effectively and has good predictive ability to guide the design of new anti-HIV drugs.Finally,the interaction patterns and mechanisms of data set compounds and new compounds with HIV-1 reverse transcriptase were studied by means of Surflex-dock docking technique.This study showed extensive interactions between the DAPY derivatives and MET230,TRP229,PHE227,TYR318,TYR183,PRO95,GLY99,ILE100,TYR188,VAL106,TYR181,GLY190,GLU138,VAL179,THR139,ASN103 and LYS101 residues in the active site of HIV-1 reverse transcriptase.These results provide useful insights for the design of potent new inhibitors of HIV-1 reverse transcriptase.4.In this paper,3D-QSAR study for 20 HIV-1 reverse transcriptase?RT?inhibitors was established using Topomer CoMFA.The model is established based on different cutting methods,and r²,q²,and Q² _extof the model are 0.920,0.575 and 0.701,respectively.The results show that the results of the two models were better.Topomer Search was used to search R-group from ZINC database.As the result,a series of R-groups with relatively high activity contribution was obtained.By No.6 molecule filtering,3 R₁ and 15 R₂ groups were selected.We employed the 3 R₁ and 15 R₂ groups to alternately substitutes for the R₁ and R₂of sample 6.Finally,45 new compounds were designed,and the Topomer CoMFA model was used to predicate the biological activity.So the Topomer Search is effective in screening and can guide the design of new HIV/AIDS drugs.Finally,the interaction mode and mechanism of the newly designed compounds with HIV-1 reverse transcriptase were studied by means of Surflex-dock docking technique.This study showed that there are extensive interactions between the 1,3,4-thiazolidinone revertase inhibitors and HIS84,ASP145,LYS33 and LEU83 residues in the active site of HIV-1 RT.These results provide useful insights for the design of potent new inhibitors of RT.5.The QSAR of 28 diaryltriazine derivatives was studied by HQSAR and Topomer CoMFA.The r² and q² of the two models are 0.972,0.749 and 0.951,0.610,respectively.The results show that the model is better.Then,the effect of the type of substituent on the activity of the compound was illustrated by the isopotential diagram and color code diagram of the two models.Using Topomer search to perform virtual screening of R groups in the ZINC molecular database,six new compounds with better activity than template molecules were designed.The pattern and mechanism of action of dataset compounds and new compounds with HIV-1 reverse transcriptase were studied by means of Surflex-dock molecular docking.This study shows some of the major amino acid residues in the receptor?eg:PRO95,HIS96,LEU168,TYR181,ILE180,PRO97,PHE171,GLY99,VAL179,LEU100,ILE178,GLY190,TRP239,LEU234,VAL180,TYP319 in the A chain,ASN137,THR139,GLU138,ASN136,ILE135 in LYS101 and B chains?form a strong interaction with the ligand molecule.