Quantitative Structure Activity Relationship Study Of Nucleoside Anti-AIDS Drugs

Human Immunodeficiency Virus?HIV-1?is the causative agent of acquired immunodeficiency syndrome?AIDS?and is a fatal infectious disease.Computer aided drug design?CADD?is an emerging discipline in which chemistry and biology are interdisciplinary.The CADD method is applied to modern pharmaceuticals,combined with new drug research and synthesis,which can save a lot of cost.Improve accuracy,save research funding,speed up the development of new drugs,improve the overall research level of the pharmaceutical industry,and provide theoretical guidance to drug research and synthesis workers.In this research.The Comparative Molecular Field Analysis?CoMFA?,Comparative Molecular Similarity Indices Analysis?CoMSIA?and Hologram Quantitative Structure-activity Relationship?HQSAR?for a series of anti-AIDS derivatives were used to have molecular active conformation selection,molecular alignment,as well as the establishment of corresponding3D-QSAR model,according to the equipotential map,the relationship between the structure and activity of the compounds was analyzed,and the molecular design was carried out by Topomer search technique.Finally,molecular docking is used to explore the binding between small molecule ligands and macromolecular proteins.The results can be further used to design new active HIV-1 reverse transcriptase inhibitors,which provides a theoretical reference for the synthesis of new drugs.The research of this paper includes the following five parts:?1?The 3D-QSAR relationship of a series of quinolone carboxylic acid derivatives was studied by Topomer CoMFA based on R group search technique.The non-cross correlation coefficient?q²?,the interaction validation coefficient?r²?and the external validation(r²_pred)were 0.790,0.890 and 0.878,respectively.The results showed that the model had good stability and prediction ability.Topomer search was used in the ZINC molecular database,as the result,6 Ra groups and 3 Rb groups were selected.Finally,we designed 12 new compounds with higher activity.A number of new quinolone carboxylic acid anti-AIDS drugs with high activity were obtained.Furthermore,molecular docking technique was used to study the mechanism of action of the three-dimensional structure of the drug and macromolecular protein.The results showed that the drug and protease Asp 30,Asp 29 and Asn 25 sites played an important role.The QSAR study could provide a theoretical reference for the synthesis of new drugs.?2?The study deals with CoMFA,CoMSIA and HQSAR to explore the important features of tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepinone?TIBO?derivatives for exerting potent HIV-1 reverse transcriptase?HIV-1 RT?inhibitors activity.The cross-validated q² value of CoMFA model is 0.641 and the non-cross-validated r² value is 0.847.The best cross-validated q² value of CoMSIA Model is 0.706 and the non-cross-vaildated r² value is 0.939.The most effective HQSAR model was obtained that the cross-validation q² value of 0.839,the non-cross-validated r² value of 0.942,the standard error of prediction SD_CVV value of 0.604,and the best hologram length value of 307 using atoms and bonds as fragment distinctions.The statistical parameters from models indicate that the data are well fitted and have high predictive ability.Furthermore,molecular docking was employed to explore the binding between small molecule ligands and macromolecular proteins which included several hydrogen bonds between the TIBO inhibitors and active site residues.Observations derived from these QSAR modeling study may be utilized further in designing promising HIV-1 reverse transcriptase inhibitors.?3?The 3D-QSAR relationship of a series of pyridone derivatives was studied by Topomer CoMFA based on R group search technique.The non-cross correlation coefficient q²,the interaction validation coefficient r² and the external validation r²_predred were 0.763,0.954 and 0.926 respectively.The results showed that the model had good stability and prediction ability.Topomer search was used in the ZINC molecular database,Finally,we designed 5 new compounds with higher activity.A number of new pyridone anti-AIDS drugs with high activity were obtained.The mechanism of action of small molecule and macromolecular protein was studied by molecular docking technique.The results showed that the drug and protease LYS 101 site played an important role.The QSAR study could provide a theoretical reference for the synthesis of new drugs.?4?Comparative Molecular Field Analysis?CoMFA?,Comparative Molecular Similarity Indices Analysis?CoMSIA?and the hologram quantitative structure-activity relationship?HQSAR?for 1-[?2-hydroxyethyloxy?methyl]-6-phenylthio thymidine?HEPT?derivatives were used to have molecular active conformation selection,molecular alignment,as well as the establishment of corresponding 3D-QSAR model.The model established by this method has a good ability to predict these compounds.The cross-validated q² value of CoMFA model is 0.565 and the non-cross-validated r² value is 0.892.The best cross-validated q² value of CoMSIA Model is 0.636 and the non-cross-vaildated r² value is 0.953.The most effective HQSAR model was obtained that the cross-validation q² value of 0.876,the non-cross-validated r² value of 0.929,and the best hologram length value is 97.Seven highly active HEPT compounds were designed based on the three-dimensional Contour maps and the HQSAR color code map,observations derived from these QSAR modeling study may be provided a theoretical reference for designing more active HEPT derivatives.?5?Topomer Comparative Molecular Field Analysis?Topomer CoMFA?and the hologram quantitative structure-activity relationship?HQSAR?for Pyrimidine derivatives were used to have molecular active conformation selection,molecular alignment,as well as the establishment of corresponding3D-QSAR model.The model established by this method has a good ability to predict these compounds.The cross-validated q² value of Topomer CoMFA model is 0.699,the non-cross-validated r² value is 0.868 and the external validation r²_predred is 0.902.The most effective HQSAR model was obtained that the cross-validation q² value of 0.814,the non-cross-validated r² value of 0.958,the best hologram length value is 97 and the component is 4.Topomer search was used in the ZINC molecular database,as the result,4 Ra groups and 5 Rb groups were selected.finally,20 new Pyrimidine derivatives compounds with high activity were obtained.The QSAR study could provide a theoretical reference for the synthesis of new drugs.