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Drug Design,Molecular Docking,and ADMET Prediction of CCR5 Inhibitors Based on QSAR Study

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Chinese Journal of Structural Chemistry 2022年第2期41卷 1-13,I0007页

作者： tong jian-bo ZHANG Xing BIAN Shuai LUO Ding College of Chemistry and Chemical Engineering Shaanxi University of Science and TechnologyXi'an 110021China Shaanxi Key Laboratory of Chemical Additives for Industry Shaanxi University of Science and TechnologyXi'an 710021China

The chemokine receptor CCR5 is a main and necessary co-receptor for which HIV can recognize and enter the cells,and has been identified as a potential new target for the design of new anti-HIV therapeutic *** active CCR5 inhibitors can prevent HIV-1 from entering target cells and block the process of *** this study,HQSAR and Topomer Co MFA methods were used to establish QSAR models for 75 1-(3,3-diphenylpropyl)-piperidinyl and urea derivatives,and cross-validation and non-cross-validation were performed on the generated *** models with good statistical parameters and reliable prediction capabilities are obtained:(Topomer Co MFA:q2 = 0.687,r2 = 0.868,r2 pred = 0.623;HQSAR:q2 = 0.781,r2 = 0.921,r2 pred = 0.636).Contour maps and color code maps provide a lot of useful information for determining structural requirements that affect *** search technology was used for virtual screening and molecular ***-dock method and ADMET technology were used to conduct molecular docking,oral bioavailability and toxicity prediction of the designed drug *** showed that A/ASN425,A/GLY198 and A/TRP427 may be the potential active residues of CCR5 inhibitors evaluated in this study,with 40 newly designed 1-(3,3-diphenylpropyl)-piperidinyl and urea derivatives which have the main ADMET properties and can be used as a reliable anti-HIV *** results provide a certain theoretical basis for the experimental verification of new compounds in the future.

关键词： HIV CCR5 inhibitors Topomer CoMFA HQSAR ADMET

3D-QSAR Study of Melittin and Amoebapore Analogues by CoMFA and CoMSIA Methods

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Chinese Journal of Structural Chemistry 2019年第2期38卷 201-210,165页

作者： tong jian-bo QIN Shang-Shang jianG Guo-Yan Shaanxi Key Laboratory of Chemical Additives for Industry Shaanxi University of Science and Technology

Peptides are one of the indispensable substances in life. The use of computer aided drug design(CADD) methods to design peptides and peptiodmimetics can short the design cycle, save research funding, improve the level of whole research to a large extent and guide the discovery of new drugs. In this paper, Melittin and amoebapore three-dimensional quantitative structureactivity relationship(3D-QSAR) models were established by using comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) method. The result shows that, the correlation coefficient(q^2) was 0.583 and non-cross-validation correlation coefficient(r^2) was 0.972 for the melittin CoMFA model. The q^2 and r^2 were 0.630 and 0.995 for the best CoMSIA model, 0.645 and 0.993 for the amoebapore CoMFA model, and 0.738 and 0.996 for the best CoMSIA model. The statistical parameters demonstrated that the CoMFA and CoMSIA models had both good predictive ability and high statistical stability, and can provide theoretical basis for designing new high activity polypeptide drugs.

关键词： 3D-QSAR melittin analogues amoebapore analogues CoMFA CoMSIA

3D-QSAR and Docking Studies of 1,3,4-Thiazolidinone Derivatives Using R-Group Search and Surflex-dock

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Chinese Journal of Structural Chemistry 2019年第3期38卷 464-475页

作者： tong jian-bo WANG Yang LEI Shan QIN Shang-Shang College of Chemistry and Chemical Engineering Shaanxi University of Science and Technology Shaanxi Key Laboratory of Chemical Additives for Industry

In this paper, a three-dimensional quantitative structure-activity relationships(3 D-QSAR) study for 20 HIV-1 reverse transcriptase(RT) inhibitors was established using Topomer Co MFA. The models were built based on different fragment cutting models, with the most effective model of the multiple correlation coefficients of fitting(r^2) to be 0.920, cross-validation(q^2) of 0.575, and external validation(Q_(ext)~2) being 0.701. The results indicated that the model obtained has both favorable estimation stability and good prediction capability. Topomer Search was used to search R-group from ZINC database. As a result, a series of R-groups with relatively high activity contribution was obtained. By No. 6 molecule filtering, 3 R_1 and 15 R_2 groups were selected, and employed to alternately substitute for the R_1 and R_2 of 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. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 RT active site, which revealed the likely bioactive conformations. 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.

关键词： QSAR RT inhibitors Topomer CoMFA Topomer search design of new inhibitors molecular docking

Comprehensive 3D-QSAR and Binding Mode of DAPY Inhibitors Using R-group Search and Molecular Docking

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Chinese Journal of Structural Chemistry 2019年第1期38卷 25-36,1页

The diarylpyrimidine(DAPY) compounds are important in the nonnucleoside reverse enzyme inhibitors. The present study is aimed at studying the three-dimensional quantitative structure-activity relationship(3D-QSAR) of DAPY inhibitors and their binding mode. We build a 3D-QSAR model involving 24 training DAPY inhibitors based on Topomer CoMFA, and 8 molecules are employed to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting, cross-validation and external validation 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 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-HIV drugs. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 reverse transcriptase active site, which revealed the likely bioactive conformations. 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.

关键词： 3D-QSAR DAPY inhibitors Topomer CoMFA Topomer search molecular docking

A 3D-QSAR Study of HIV-1 Integrase Inhibitors Using RASMS and Topomer CoMFA

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Chinese Journal of Structural Chemistry 2019年第6期38卷 867-881页

作者： tong jian-bo QIN Shang-Shang LEI Shan WANG Yang Shaanxi Key Laboratory of Chemical Additives for Industry Shaanxi University of Science and Technology

Acquired Immunodeficiency Syndrome(AIDS) is a significant human health threat around the world. Therefore, the study of anti-human immunodeficiency virus(HIV) drug design has become an important task for today’s society. In this paper, a three-dimensional quantitative structure-activity relationships study(3 D-QSAR) was conducted on 53 HIV-1 integrase inhibitors(IN) using random sampling analysis on molecular surface(RASMS) and Topomer comparative molecular field analysis(Topomer CoMFA). The multiple correlation coefficients of fitting, cross-validation, and external validation of two models were 0.926, 0.815 and 0.908 and 0.930, 0.726 and 0.855, respectively. The results indicated that two models obtained had both favorable estimation stability and good prediction capability. Topomer Search was used to search appropriate R groups from ZINC database, and 28 new compounds were designed thereby. The Topomer CoMFA model was subsequently used to predict the biological activity of these compounds, showing that 24 of the new compounds were more active than the template molecule. 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 design of even more effective HIV/AIDS drugs.

关键词： 3D-QSAR integrase inhibitors RASMS Topomer CoMFA molecular docking

QSAR Study of Thieno [2,3-d] Pyrimidine as a Promising Scaffold Using HQSAR, CoMFA and CoMSIA

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Chinese Journal of Structural Chemistry 2021年第5期40卷 565-575,528页

作者： tong jian-bo FENG Yi WANG Tian-Hao ZHANG Xing College of Chemistry and Chemical Engineering Shaanxi University of Science and TechnologyXi'an 710021China Shaanxi Key Laboratory of Chemical Additives for Industry Shaanxi University of Science and TechnologyXi'an 710021China Key Laboratory of Chemical Additives for China National Light Industry Shaanxi University of Science and TechnologyXi'an 710021China

In this study, Co MFA, Co MSIA and HQSAR techniques were used to study the important characteristic activities of thieno [2,3-d] pyrimidine derivatives for effective antitumor activity. The q^(2) value of cross validation of CoMFA model was 0.621, and r^(2) value of non-cross validation was 0.959. The best cross validation q^(2) value of CoMSIA model was 0.522, while the r^(2) value of non-cross validation was 0.961. The most effective HQSAR model was obtained by taking atoms and bonds as fragments: the q^(2) value of cross validation is 0.535, the r^(2) value of non-cross validation is 0.871, the standard error of prediction is 0.488, and the optimal hologram length is 199. The statistical parameters from the model show that the data fit well and have high prediction ability. In addition, molecular docking is used to study the binding requirements between ligands and receptor proteins, including several hydrogen bonds between thieno [2,3-d] pyrimidine and active site residues. The results obtained from these QSAR modeling studies can be used to design promising anticancer drugs.

关键词： thieno[2 3-d]pyrimidine CoMFA CoMSIA HQSAR molecular dock

Topomer CoMFA, HQSAR Studies and Molecular Docking of 2,5-Diketopiperazine Derivatives as Oxytocin Inhibitors

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Chinese Journal of Structural Chemistry 2020年第8期39卷 1385-1394,1357页

作者： tong jian-bo FENG Yi WANG Tian-Hao WU Lu-Yang College of Chemistry and Chemical Engineering Shaanxi University of Science and TechnologyXi'an 710021China Shaanxi Key Laboratory of Chemical Additives for Industry Xi'an 710021China

Topomer comparative molecular field analysis(Topomer Co MFA)and holographic quantitative structure-activity relationship(HQSAR)for 1302,5-diketopiperazine derivatives were used to build a three-dimensional quantitative structure-activity relationship(3D-QSAR)*** results show that the models have high predictive *** Topomer CoMFA,the cross-validated q^2 value is 0.710 and the non-cross-validated r^2 value is *** most effective HQSAR model shows that the cross-validation q^2 value is 0.700,the non-cross-validated r^2 value is 0.815,and the best hologram length value is 353 using connections and bonds as fragment distinctions.50 highly active 2,5-diketopiperazine derivatives were designed based on the three-dimensional equipotential map and HQSAR color code ***,the molecular docking method was also used to study the interactions of these new molecules by docking the ligands into the diketopiperazine active site,which revealed the likely bioactive *** study showed that there are extensive interactions between the new molecule and Arg156,Arg122 residues in the active site of *** results provide useful insights for the design of potent of the new 2,5-diketopiperazine derivatives.

关键词： three-dimensional quantitative structure-activity relationship Topomer CoMFA HQSAR 2,5-diketopiperazine derivatives

QSAR and Docking Studies of Thiazolidine-4-carboxylic Acid Derivatives as Neuraminidase Inhibitors

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Chinese Journal of Structural Chemistry 2020年第4期39卷 651-661页

作者： tong jian-bo WANG Tian-Hao WU Ying-Ji FENG Yi College of Chemistry and Chemical Engineering Shaanxi University of Science and TechnologyXi’an 710021China Shaanxi Key Laboratory of Chemical Additives for Industry Xi’an 710021China

In order to understand the chemical-biological interactions governing their activities toward neuraminidase(NA),QSAR models of 28 thiazolidine-4-carboxylic acid derivatives with inhibitory influenza A virus were *** 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 *** correlation coefficient(R2)of established MLR model was 0.984,and the cross-validated correlation coefficient(Q2)of MLR model was ***,the cross-validated correlation coefficient for the test set(Qext 2)was *** binding mode pattern of the compounds to the binding site of integrase enzyme was confirmed by docking *** results of present study indicated that this model can aid in designing more potent neuraminidase inhibitors.

关键词： 3D-QSAR thiazolidine-4-carboxylic acid derivatives 3D-HoVAIF molecular designing molecular docking

QSAR Study and Molecular Design of Isoquinolone Derivative JNK1 Inhibitors

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Chinese Journal of Structural Chemistry 2021年第12期40卷 1586-1594,1551页

作者： tong jian-bo XIAO Xue-Chuna LUO Ding XU Hai-Yin WANG Jie College of Chemistry and Chemical Engineering Shaanxi University of Science and TechnologyXi'an 710021China Shaanxi Key Laboratory of Chemical Additives for Industry Xi'an 710021China

JNK1 is a drug target for the treatment of type 2 diabetes,and it plays a key mediator role in metabolic *** this paper,holographic quantitative structure-activity relationship(HQSAR)technology and Topomer comparative molecular field analysis(Topomer CoMFA)technology are used to analyze the quantitative structure-activity relationship(QSAR)of 39 isoquinolone *** cross validation correlation coefficient(q^(2))is 0.696(Topomer CoMFA)and 0.826(HQSAR),and the non-cross validation correlation coefficient(r^(2))is 0.935(Topomer CoMFA)and 0.987(HQSAR).The results showed that the models have good stability and predictive *** Topomer search module was applied to define high contribution fragments in the ZINC database,designing 20 new isoquinolone compounds with theoretically high inhibitory *** molecular docking was carried out to explore the interaction between the ligand and target JNK1 *** study can provide a theoretical basis for the design of new JNK1 inhibitors.

关键词： Topomer CoMFA HQSAR molecular docking isoquinolone derivatives molecular design