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Three-dimensional Quantitative Structure-activity Relationship Models of hiv-1 integrase Inhibitors of DKAs

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Chinese Journal of Structural Chemistry 2012年第12期31卷 1769-1781页

作者：张美青赵文娜陆绍永 Department of Chemistry Zhejiang University Key Laboratory for Molecular Design and Nutrition Engineering Ningbo Institute of Technology Zhejiang University

As one of the three viral encoded enzymes of hiv-1 infection, hiv-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of hiv-1 IN. In the present work, two three-dimensional QSAR techniques （CoMFA and CoMSIA） were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search （AOS） and all-placement search （APS） were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the hiv-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent hiv-1 integrase inhibitors.

关键词： hiv-1 integrase diketo acids CoMFA CoMSIA 3D-QSAR

Building the Pharmacophore Model of hiv-1 integrase Strand Transfer Inhibitors and Studying Their Inhibition Mechanism

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Chinese Journal of Structural Chemistry 2010年第4期29卷 575-581页

作者：吴可柱李爱秀刘兴太蔡德海马翼 Drug Design Laboratory of the Basic Science Department Medical College of Chinese People's Armed Police Force Department of Pharmacy Jiangxi Provincial Corps Hospital of Chinese People's Armed Police Force Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard Medical College of Chinese People's Armed Police Force State Key Laboratory of Elemento-organic Chemistry Nankai University

The replication of hiv-1 requires the integration of its cyclic DNA into host DNA by hiv-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by hiv-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of hiv-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the hiv-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.

关键词： hiv-1 integrase strand transfer inhibitors pharmacophore model molecular docking mechanism

Pharmacophore and Docking-based 3D-QSAR Studies on hiv-1 integrase Inhibitors

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Chemical Research in Chinese Universities 2014年第2期30卷 297-305页

作者： ZHANG Xiaoyi DENG Dongjie TAN Jianjun HE Yu LI Chunhua WANG Cunxin College of Life Science and Bioengineering Beijing University of Technology Beijing 100124 P.R.China College of Materials Science and Engineering Beijing University of Technology Beijing 100124 P.R.China

integrase（IN） plays an essential role in the process of hiv-1 *** inhibitors of diketo acid derivatives（DKAs） were analysed by the Comparative Molecular Field Analysis（CoMFA） and Comparative Molecular Similarity Induces Analysis（CoMSIA） methods.A set of 42 compounds were randomly selected as the training set（35） and test set（7）.Firstly,a good pharmacophore（goodness of hit=0.787） was obtained and used to align ***,predictive models were constructed with the CoMFA and CoMSIA methods based on the pharmacophore *** a result,the CoMS1A method yielded the best model with an r2 of 0.955 and a q2 of 0.665,which can predict the activities of the tested DKAs very well（r2=0.559）.Finally,DKAs were docked into IN,and the predicit modes were superimposed on the contour maps obtained from the best CoMSIA *** superimposed maps gave a visualized and meaningful insight into the inhibitory behaviors,providing significantly useful information for the rational drug design of anti-IN agents.

关键词： hiv-1 integrase Diketo acid Quantitative structure-activity relationship Pharmacophore Molecular docking

Synthesis and hiv-1 integrase Inhibitory Activity of Furanone Derivatives

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Chemical Research in Chinese Universities 2010年第2期26卷 225-229页

作者： YU Sheng-hui ZHAO Si-tai LIU Chuan ZHONG Yuan ZHAO Gui-sen School of Pharmaceutical Sciences Shandong University Jinan 250012 P R. China

Twenty novel furanone derivatives, based on the structure of raltegravir which was the first hiv-1 inte- grase（IN） inhibitor approved by the United States Food and Drug Administration（US FDA）, were designed, synthesized and characterized by ^1H NMR, IR and MS. The biological activities of these compounds against hiv-1 IN in vitro were evaluated. The assay results indicate that the replacement of pyrimidinone with furanone decreased the inhibitory activity of the compounds to hiv-1 IN. Compounds 3i, 3j and 3t show moderate inhibitory activity against hiv-1 IN and selectively inhibit the strand transfer reaction.

关键词： hiv-1 integrase Diketoacid Furanone

Molecular Mechanism of hiv-1 integrase-vDNA Interactions and Strand Transfer Inhibitor Action:A Molecular Modeling Perspective

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Molecular Mechanism of HIV-1 Integrase-vDNA Interactions and...

Synthesis, Crystal Structure and Biological Activity of Dimethyl 1-Methyl-1,4-dihydroquinoline-3,4-dicarboxylate and Tetramethyl Pyrrolo-[1,2-a]quinoline-2,3,4,5-tetracarboxylate

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作者：薛伟伟刘焕香姚小军 State Key Laboratory of Applied Organic Chemistry and Department of Chemistry Lanzhou UniversityLanzhou 730000China School of Pharmacy Lanzhou UniversityLanzhou730000China

＜正＞Human immunodeficiency virus type 1（hiv-1） integrase（IN） is a promising therapeutic target for developing anti-AIDS ***,the elucidation of the structure of hiv-1 IN complexed with viral DNA（vDNA） and the inhibition action of hiv-1 IN strand-transfer inhibitor raltegravir（RAL,approved by FDA in 2007） has been proved to be a great ***,we report on a computational model of hiv-1 IN-vDNA-RAL using the crystal structure of prototype foamy virus（PFV） intasome as a ***,molecular dynamics（MD） simulation was carried out to identify the key contact residues of the IN binding to vDNA as well as the conformation changes of the IN residues and vDNA nucleotides at the ***,a possible RAL binding and inhibition mechanism was also proposed,which provides a new chance and a reliable platform for the structure-based drug design and discovery targeting integration process of hiv-1.

关键词： hiv-1 integrase protein-DNA interactions raltegravir molecular dynamics simulation free energy calculation

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Chinese Journal of Structural Chemistry 2020年第7期39卷 1271-1276页

作者： XU Xue-Mei LUO Zai-Gang HAN Xin-Xin LIU Qian-Nan LI Rui College of Chemical Engineering Anhui University of Science and TechnologyHuainan 232001China

The target compounds 3(C14H15NO4)and 4(C20H17NO8)were synthesized and structurally determined by single-crystal X-ray *** crystal of 3 is in the monoclinic system,space group P21/c with a=7.3017(3),b=7.8737(5),c=22.4227(11)?,β=94.837(5)°,C14H15NO4,Mr=261.27,Dc=1.351 g/cm3,V=1284.51(11)?3,Z=4,F(000)=552,μ(MoKa)=0.828 mm–1,T=289.12(10)K,2236 independent reflections with 1827 observed ones(I>2σ(I)),R=0.0515 and w R=0.1394 with GOF=1.044(R=0.0605 and w R=0.1548 for all data).The crystal of compound 4 is in the monoclinic system,space group P21/c with a=7.1269(3),b=12.6518(6),c=20.7540(8)?,β=96.941(4)°,C20H17NO8,Mr=399.35,Dc=1.428 g/cm3,V=1857.61(14)?3,Z=4,F(000)=832.0,μ(MoKa)=0.950 mm–1,T=288.81(10)K,3216 independent reflections with 2253 observed ones(I>2σ(I)),R=0.0612 and wR=0.1548 with GOF=1.055(R=0.0824 and w R=0.1790 for all data).The skeleton of 1,4-dihydroquinoline 3 is noncoplanar,while pyrrolo[1,2-a]-quinoline 4 owns a coplanar frame ***-dimensional interaction model of compound 4 was formed by the one kind ofπ-πinteraction between the two adjacent molecules at upper and lower *** the inhibition to the strand transfer process of hiv-1 integrase of the title compounds was also evaluated.

关键词： 1,4-dihydroquinoline pyrrolo[1,2-a]quinoline synthesis crystal structure hiv-1 integrase

Synthesis,Crystal Structure and Biological Activity of 25,27-Di(α,γ-diketo-p-methylphenylbutoxy)-26,28-dihydroxy p-tert-butylcalix[4]arene

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Chinese Journal of Structural Chemistry 2014年第6期33卷 865-870页

作者：罗再刚马超吴丽梅袁梦鸿徐传豪胡劲松徐雪梅 College of Chemical Engineering Anhui University of Science & Technology

The title complex（C66H76O8·CH3CN） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 22.384（13）, b = 13.413（7）, c = 21.867（12）, β = 112.257（7）°, C68H78NO8, Mr = 1037.31, Dc = 1.133 g/cm3, V = 6076（6） 3, Z = 4, F（000） = 2224, μ（MoKa） = 0.073 mm-1, T = 296（2） K, 10276 independent reflections with 5469 observed ones（I 〉 2σ（I））, R = 0.0797 and wR = 0.2316 with GOF = 1.027（R = 0.1442 and wR = 0.2689 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O–H···O hydrogen bonds. The inhibition of the strand transfer process of hiv-1 integrase of the title compound was also evaluated. Preliminary bioassays indicated that it has a low inhibition ratio（24.85%） at the concentration of 50 μM.

关键词： p-tert-butylcalixarene derivative α γ-diketo synthesis crystal structure hiv-1 integrase

Synthesis, Crystal Structure and Anti-integrase Activity of 25,27-Bis[(Z)-4-(p-methoxyphenyl)-4-hydroxybut-3-en-2-one-1-methyl]-26,28-dihydroxycalix[4]arene

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Chinese Journal of Structural Chemistry 2014年第8期33卷 1117-1122页

作者：罗再刚赵禹马超曹露艾少华胡劲松徐雪梅 College of Chemical Engineering Anhui University of Science & Technology

The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 19.434（5） A, β = 104.411（4）°, Mr = 804.85, Dc = 1.288 g/cm3, V = 4149.2（17） A3, Z = 4, F（000） = 1696, #（MoKa） = 0.089 mm-1T = 296（2） K, 7279 independent reflections with 3172 observed ones （I 〉 2δ（/））, R = 0.0520 and wR = 0.1203 with GOF = 0.928 （R = 0.1464 and wR = 0.1657 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O-H…O hydrogen bonds. Preliminary bioassays indicated that the title compound has a potent inhibitory activity against the strand transfer process of hiv-1 integrase.

关键词： calixarene derivative 1,3-diketo hiv-1 integrase crystal structure

Synthesis and Crystal Structure of 6-Cyclohexyl-8-methylphenanthridine

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Chinese Journal of Structural Chemistry 2021年第10期40卷 1284-1290页

作者： LUO Zai-Gang WEI Dan-Dan PENG Cheng-Tong LIU Chen-Fu CHEN Qi-Hua ZHANG Rong-Hao XU Xue-Mei State Key Laboratory of Mining Response and Disaster Prevention and Control in Deep Coal Mines College of Chemical EngineeringAnhui University of Science and TechnologyHuainan 232001China School of Pharmaceutical Science Gcwnan Medical UniversityGanzhou 341000China

The target compound Ⅳ (C_(20)H_(21)N) was synthesized through four-step reactions and structurally determined by single-crystal X-ray *** crystal of compound Ⅳ is in the orthorhombic system,space group Fdd2 with a=41.178(19),b=30.389(8),c=4.8182(17)Å,β=90°,C_(20)H_(21)N,M_(r)=275.38,D_(c)=1.213g/cm^(3),V=6029(4)Å^(3),Z=16,F(000)=2368,μ(Mo Ka)=0.527 mm^(-1),T=240(2) K,2200 independent reflections with 1233 observed ones (I>2σ(I)),R=0.1285 and w R=0.2589 with GOF=1.050 (R=0.2058 and w R=0.3055for all data).A one-dimensional interaction model of the title compound was formed by one kind of π-π interactions between the two phenyl rings of the adjacent molecules at upper and lower *** inhibition to the strand transfer process of hiv-1 integrase of the target compound was also evaluated.

关键词： phenanthridine synthesis crystal structure hiv-1 integrase

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