共查询到17条相似文献,搜索用时 171 毫秒
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采用分子动力学和分子力学相结合的方法,研究了一类1,2-萘醌类抑制剂与酪氨酸蛋白磷酸酯酶PTP1B之间的相互作用模式.计算得到的抑制剂和靶酶之间的相互作用模式显示范德华相互作用、疏水相互作用以及氢键作用是主要的作用模式.计算结果还表明抑制剂和PTP1B的相互作用能△E越低,抑制剂活性越高.通过计算各种能量对△E的贡献,以及对复合物结构参数的分析,发现抑制剂和受体之间疏水相互作用是造成抑制剂活性差别的主要原因.这为设计其他非酸类抑制剂提供了信息. 相似文献
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两类HPPD酶抑制剂的比较分子场分析研究 总被引:2,自引:0,他引:2
用比较分子场分析法(CoMFA)研究了环已二酮类及3-烷基酸-2-环已烯酯类化 合物的结构与活性的关系。本研究从蛋白酶与底物动力学模拟的复合物结构出发构 建两类抑制剂化合物分子的构象,并进行了全空间搜索,CoMFA分析得到了较好的 模型(交叉验证回归系数q~2 = 0.779,模型的线性回归系数r~2 = 0.989)。该方 程不仅可以帮助推测抑制剂与受体的结合方式,还可定量地预测结构相近的类似物 活性,为设计合成新的HPPD酶抑制剂提供了理论依据。 相似文献
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用分子对接方法研究了一系列芳香二酮酸类抑制剂与HIV-1整合酶的识别及相互作用. 结果表明, 抑制剂结合到整合酶Asp64~Leu68, Thr115~Phe121, Gln148~Lys159和Mg2+所构成的口袋区, 抑制机理与5CITEP相似. 采用分子动力学模拟和MM/PBSA方法计算了芳香二酮酸类抑制剂与整合酶之间的结合自由能, 计算结果与实验值相吻合, 平均绝对偏差为3.6 kJ/mol, 体系范德华相互作用和溶剂化效应的非极性项是利于形成复合物的主要因素. 相关性分析结果表明, 结合自由能值与疏水相互作用有较强的线性相关(R=0.61), 基于此, 用多元线性回归方法给出了一个能较强预测芳香二酮酸类抑制剂与HIV-1整合酶的结合自由能预测模型, 为后续基于抑制剂结构的抗HIV-1药物分子设计提供指导. 相似文献
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蛋白激酶A(PKA)和蛋白激酶C(PKC)的过度表达导致细胞生长分化异常,是治疗肿瘤的潜在靶点.抑制剂BD2对PKA和PKC抑制作用存在高选择性.为了探讨BD2高选择性机制,本工作以PKA与BD2复合物的晶体结构为模板,通过同源模建结合分子对接的方法构建PKC βⅡ与BD2复合物的结构,并对PKA-BD2复合物和PKC-BD2复合物进行了2.5 ns的分子动力学模拟,运用MM-GBSA方法计算了结合自由能,通过能量分解的方法考察PKA和PKC的主要残基与BD2之间的相互作用和识别机制.结合能分析结果很好地描述了BD2对PKA抑制活性比其对PKC抑制活性高这一实验现象.氢键分析和能量分解结果共同说明了BD2的B环和酰胺链部分与PKA和PKC中相应位点的残基之间的相互作用存在差异,这是BD2存在选择性的内在因素.BD2高选择性作用机制的阐明为进一步基于结构的balanol类抑制剂的结构设计和优化提供了合理的指导. 相似文献
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蛋白激酶A (PKA)和蛋白激酶C (PKC)的过度表达导致细胞生长分化异常, 是治疗肿瘤的潜在靶点. 抑制剂BD2对PKA和PKC抑制作用存在高选择性. 为了探讨BD2高选择性机制, 本工作以PKA与BD2复合物的晶体结构为模板, 通过同源模建结合分子对接的方法构建PKC βII与BD2复合物的结构, 并对PKA-BD2复合物和PKC-BD2复合物进行了2.5 ns的分子动力学模拟, 运用MM-GBSA方法计算了结合自由能, 通过能量分解的方法考察PKA和PKC的主要残基与BD2之间的相互作用和识别机制. 结合能分析结果很好地描述了BD2对PKA抑制活性比其对PKC抑制活性高这一实验现象. 氢键分析和能量分解结果共同说明了BD2的B环和酰胺链部分与PKA和PKC中相应位点的残基之间的相互作用存在差异, 这是BD2存在选择性的内在因素. BD2高选择性作用机制的阐明为进一步基于结构的balanol类抑制剂的结构设计和优化提供了合理的指导. 相似文献
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A method was validated for the determination of the 2 main components of bee venom, phospholipase A2 and melittin, by capillary electrophesis (CE). Optimum resolution and selectivity were attained with a running electrolyte of 150 mM phosphoric acid, pH 1.8. The repeatability and day-to-day reproducibility of the migration times were better than 0.36 and 2.8%, respectively. The repeatability and day-to-day reproducibility of the normalized peak areas were better than 1.3 and 2.6%, respectively. The response of the UV detector at 190 nm was linear over < 2 concentration decades, from 0.05 to 1.5 mg/mL, with correlation coefficients of 0.9994 for phospholipase A2 and 0.9997 for melittin. The limits of detection and quantitation were 4.5 and 15 microg/mL, respectively, for phospholipase A2 and 1.6 and 6 microg/mL, respectively, for melittin. The reproducibility of the measurements with 2 different CE instruments was satisfactory; the mean concentration and relative standard deviation (RSD) values for phospholipase A2 and melittin were 14.4% (RSD, 1.3%) and 51.4% (RSD, 1.1%), respectively, with instrument I; the corresponding values with instrument II were 14.5% (RSD, 2.8%) and 52.3% (RSD, 2.2%). The accuracy was estimated by comparison with a liquid chromatographic (LC) method. Differences between the CE and LC measurements were attributed to irreversible adsorption of the analytes on the LC column. The recoveries of phospholipase A2 and melittin with the CE method were 98.8 and 101.7%, respectively. 相似文献
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Mouchlis VD Michopoulou V Constantinou-Kokotou V Mavromoustakos T Dennis EA Kokotos G 《Journal of chemical information and modeling》2012,52(1):243-254
The group IVA cytosolic phospholipase A(2) (GIVA cPLA(2)) plays a central role in inflammation. Long chain 2-oxoamides constitute a class of potent GIVA cPLA(2) inhibitors that exhibit potent in vivo anti-inflammatory and analgesic activity. We have now gained insight into the binding of 2-oxoamide inhibitors in the GIVA cPLA(2) active site through a combination of molecular docking calculations and molecular dynamics simulations. Recently, the location of the 2-oxoamide inhibitor AX007 within the active site of the GIVA cPLA(2) was determined using a combination of deuterium exchange mass spectrometry followed by molecular dynamics simulations. After the optimization of the AX007-GIVA cPLA(2) complex using the docking algorithm Surflex-Dock, a series of additional 2-oxoamide inhibitors have been docked in the enzyme active site. The calculated binding affinity presents a good statistical correlation with the experimental inhibitory activity (r(2) = 0.76, N = 11). A molecular dynamics simulation of the docking complex of the most active compound has revealed persistent interactions of the inhibitor with the enzyme active site and proves the stability of the docking complex and the validity of the binding suggested by the docking calculations. The combination of molecular docking calculations and molecular dynamics simulations is useful in defining the binding of small-molecule inhibitors and provides a valuable tool for the design of new compounds with improved inhibitory activity against GIVA cPLA(2). 相似文献
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In structure-based design of phospholipase A2 inhibitors, comparative molecular field analysis is performed on known phospholipase A2 (PLA2) inhibitors to build a pseudo-receptor map of the enzyme, which is compared to maps from probe searches with proton and methane. The pseudo-receptor map resembled in steric properties to the map from a probe search. Hence known ligands can be used to deduce the shape and chemical properties of the binding site of a receptor. Useful information for drug design can be obtained from such receptor mapping. 相似文献
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To understand pharmacophore properties of pyranmycin derivatives and to design novel inhibitors of 16S rRNA A site, comparative molecular field analysis (CoMFA) approach was applied to analyze three-dimensional quantitative structure–activity relationship (3D-QSAR) of 17 compounds. AutoDock 3.0.5 program was employed to locate the orientations and conformations of the inhibitors interacting with 16S rRNA A site. The interaction mode was demonstrated in the aspects of inhibitor conformation, hydrogen bonding and electrostatic interaction. Similar binding conformations of these inhibitors and good correlations between the calculated binding free energies and experimental biological activities suggest that the binding conformations of these inhibitors derived from docking procedure were reasonable. Robust and predictive 3D-QSAR model was obtained by CoMFA with q2 values of 0.723 and 0.993 for cross-validated and non-cross-validated, respectively. The 3D-QSAR model built here will provide clear guidelines for novel inhibitors design based on the Pyranmycin derivatives against 16S rRNA A site. 相似文献
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A novel class of inhibitors for human steroid 5 alpha-reductase: phenoxybenzoic acid derivatives. I.
S Igarashi T Kimura R Naito H Hara M Fujii H Koutoku H Oritani T Mase 《Chemical & pharmaceutical bulletin》1999,47(8):1073-1080
In a search for novel nonsteroidal inhibitors of human prostatic 5 alpha-reductase, we found a new series of phenoxybenzoic acid derivatives to be potent human prostatic 5 alpha-reductase inhibitors. Among them, 4-(biphenyl-4-yloxy)benzoic acid derivatives (2n, YM-31758), 2o and 2s showed more potent inhibitory activities than finasteride with IC50 values of 0.87, 0.67 and 0.56 nM, respectively. The optimized structures for the phenoxybenzoic acid derivatives 2d-2i were calculated by molecular modeling analysis, and the favorable distance between the carbon of the carboxyl group and the centroid of the phenyl group (benzene ring C) was found to be in the 9-11 A range. 相似文献
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Significant studies on phospholipases optimization, characterization, physiological role and industrial potential have been
conducted worldwide. Some of them have been directed for biotechnological advances such as gene discovery and functional enhancement
by protein engineering. Others reported phospholipases as virulence factor and major cause of pathophysiological effects.
A general overview on phospholipase is needed for the identification of new reliable and efficient phospholipase, which would
be potentially used in number of industrial and medical applications. Phospholipases catalyse the hydrolysis of one or more
ester and phosphodiester bonds of glycerophospholipids. They vary in site of action on phospholipid which can be used industrially
for modification/production of new phospholipids. Catalytically active phospholipase mainly use phosphatidylcholine as major
substrate, but they can also show specificity with other phospholipids. Several accurate phospholipase assay methods are known,
but a rapid and reliable method for high-throughput screening is still a challenge for efficient supply of superior phospholipases
and their practical applications. Major application of phospholipase is in industries like oil refinery, health food manufacturing,
dairy, cosmetics etc. All types of phospholipases can be involved as virulence factor. They can also be used as diagnostic
markers for microbial infection. The importance of phospholipase in virulence is proven and inhibitors of the enzyme can be
used as candidate for preventing the associated disease. 相似文献