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91.
We report our three-dimensional quantitative structure activity relationship (3D-QSAR) studies of the series of anilinopyrimidine derivatives of JNK1 inhibitors. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied using different alignment methods. The ligand-based atom-by-atom matching alignment has produced better values for CoMFA (q(2) = 0.646 and r(2) = 0.983), while in CoMSIA it has achieved only lower statistical values. The pharmacophore-based model has produced (q(2) = 0.568, r(2) = 0.938) and (q(2) = 0.670, r(2) = 0.982) for CoMFA and CoMSIA models, respectively. As the model was based on the receptor-guided alignment, all the compounds were optimized within the receptor, resulting in q(2) = 0.605 and r(2) = 0.944 for CoMFA, and q(2) = 0.587 and r(2) = 0.863 for CoMSIA. Molecular Dynamic simulation studies suggested that the generated models were consistent with the low-energy protein ligand conformation. The CoMFA and CoMSIA contour maps indicated that the substitutions of the electropositive groups in the phenyl ring, and an addition of hydrophobic groups in the pyrimidine ring, are important to enhance the activity of this series. Moreover, the virtual screening analysis against NCI database yields potentials hits, and the results obtained would be useful to synthesize selective and highly potent c-Jun N-terminal kinase 1 analogs. 相似文献
92.
Six structurally similar sulfonamide haptens have been linked to ovalbumin by diazo-method used as coating antigen. An enzyme-linked immunosorbent assay (ELISA) was developed to investigate heterologous structure of coating haptens on sensitivity of ELISA for sulfamethazine. The sensitivities of ELISA, expressed as IC50 values, ranged from 94 to 877 ng mL? 1 when six coating antigens were employed. The results suggested that the structural heterology of coating hapten had significant effect on ELISA sensitivity. In order to evaluate the relationship between the degree of hapten heterology and ELISA sensitivity, we used molecular similarity methods to qualitatively represent the degree of coating hapten heterology. The Molecular Access System (MACCS) structural keys and the Tanimoto similarity coefficient were used to calculate and compare the degree of coating hapten's similarity, and the authors found that the sensitivity of ELISA was not in direct proportion with degree of coating hapten heterology in the case of study. 相似文献
93.
目的:利用紫外光谱相似度考察注射用丹参粉针(冻干)与6种输液配伍后的稳定性。方法:模拟临床用药方法,将注射用丹参与氯化钠注射液(0.9%)、葡萄糖注射液(5%)、复方氯化钠注射液、复方右旋糖酐40注射液、右旋糖酐40葡萄糖注射液、果糖注射液配伍,测定配伍后7h内配伍液的pH值及UV吸收度,根据UV吸收值计算紫外光谱相似度及其变化。结果:6种配伍液7h内pH值无明显变化;在200nm一400nm范围内,注射用丹参与6种输液配伍的平均相似度大小依次为5%葡萄糖注射液〉复方氯化钠注射液〉0.9%氯化钠注射液〉右旋糖酐40葡萄糖注射液〉复方右旋糖酐40注射液〉果糖注射液;配伍液在250.5~300nm范围内相似度较大;配伍液相似度变化随时间延长逐渐减小。结论:注射用丹参与氯化钠注射液(0.9%)、葡萄糖注射液(5%)、复方氯化钠注射液配伍后较稳定;与右旋糖酐40葡萄糖注射液、复方右旋糖酐40注射液及果糖注射液输液配伍后相似度较小.应谨慎使用。 相似文献
94.
Thorsteinson N Ban F Santos-Filho O Tabaei SM Miguel-Queralt S Underhill C Cherkasov A Hammond GL 《Toxicology and applied pharmacology》2009,234(1):47-441
Anthropogenic compounds with the capacity to interact with the steroid-binding site of sex hormone binding globulin (SHBG) pose health risks to humans and other vertebrates including fish. Building on studies of human SHBG, we have applied in silico drug discovery methods to identify potential binders for SHBG in zebrafish (Danio rerio) as a model aquatic organism. Computational methods, including; homology modeling, molecular dynamics simulations, virtual screening, and 3D QSAR analysis, successfully identified 6 non-steroidal substances from the ZINC chemical database that bind to zebrafish SHBG (zfSHBG) with low-micromolar to nanomolar affinities, as determined by a competitive ligand-binding assay. We also screened 80,000 commercial substances listed by the European Chemicals Bureau and Environment Canada, and 6 non-steroidal hits from this in silico screen were tested experimentally for zfSHBG binding. All 6 of these compounds displaced the [3H]5α-dihydrotestosterone used as labeled ligand in the zfSHBG screening assay when tested at a 33 μM concentration, and 3 of them (hexestrol, 4-tert-octylcatechol, and dihydrobenzo(a)pyren-7(8H)-one) bind to zfSHBG in the micromolar range. The study demonstrates the feasibility of large-scale in silico screening of anthropogenic compounds that may disrupt or highjack functionally important protein:ligand interactions. Such studies could increase the awareness of hazards posed by existing commercial chemicals at relatively low cost. 相似文献
95.
Zheng B Mello-Thoms C Wang XH Abrams GS Sumkin JH Chough DM Ganott MA Lu A Gur D 《Academic radiology》2007,14(8):917-927
RATIONALE AND OBJECTIVES: The clinical utility of interactive computer-aided diagnosis (ICAD) systems depends on clinical relevance and visual similarity between the queried breast lesions and the ICAD-selected reference regions. The objective of this study is to develop and test a new ICAD scheme that aims improve visual similarity of ICAD-selected reference regions. MATERIALS AND METHODS: A large and diverse reference library involving 3,000 regions of interests was established. For each queried breast mass lesion by the observer, the ICAD scheme segments the lesion, classifies its boundary spiculation level, and computes 14 image features representing the segmented lesion and its surrounding tissue background. A conditioned k-nearest neighbor algorithm is applied to select a set of the 25 most "similar" lesions from the reference library. After computing the mutual information between the queried lesion and each of these initially selected 25 lesions, the scheme displays the six reference lesions with the highest mutual information scores. To evaluate the automated selection process of the six "visually similar" lesions to the queried lesion, we conducted a two-alternative forced-choice observer preference study using 85 queried mass lesions. Two sets of reference lesions selected by one new automated ICAD scheme and the other previously reported scheme using a subjective rating method were randomly displayed on the left and right side of the queried lesion. Nine observers were asked to decide for each of the 85 queried lesions which one of the two reference sets was "more visually similar" to the queried lesion. RESULTS: In classification of mass boundary spiculation levels, the overall agreement rate between the automated scheme and an observer is 58.8% (Kappa = 0.31). In observer preference study, the nine observers preferred on average the reference lesion sets selected by the automated scheme as being more visually similar than the set selected by the subjective rating approach in 53.2% of the queried lesions. The results were not significantly different for the two methods (P = .128). CONCLUSIONS: This study suggests that using the new automated ICAD scheme, the interobserver variability related issues can thus be avoided. Furthermore, the new scheme maintains the similar performance level as the previous scheme using the subjective rating method that can select reference sets that are significantly more visually similar (P < .05) than when using traditional ICAD schemes in which the mass boundary spiculation levels are not accurately detected and quantified. 相似文献
96.
Jixin Liu Jimin Liang Wei Qin Jie Tian Kai Yuan Lijun Bai Yi Zhang Wei Wang Yarong Wang Qiang Li Liyan Zhao Lin Lu Karen M. von Deneen Yijun Liu Mark S. Gold 《Neuroscience letters》2009
Recent functional neuroimaging studies have examined cognitive inhibitory control, decision-making and stress regulation in heroin addiction using a cue-reactivity paradigm. Few studies have considered impairments in heroin users from an integrated perspective for evaluation of their brain functions. We hypothesized that the brain regions that are dysregulated in the chronic heroin users during cue-reactivity studies may also show dysfunctional connectivity in memory, inhibition and motivation-related dysfunctions during a resting state free of cues. The present study used resting functional magnetic resonance imaging (fMRI) to compare the interaction of brain regions between 12 chronic heroin users and 12 controls by employing a novel graph theory analysis (GTA) method. As a data-driven approach, GTA has the advantage of evaluating the strength as well as the temporal and spatial patterns of interactions among the brain regions. Abnormal topological properties were explored in the brain of chronic heroin users, such as the dysfunctional connectivity in the prefrontal cortex, ACC, SMA, ventral striatum, insula, amygdala and hippocampus. Our results suggest that GTA is a useful tool in defining dysregulated neural networks even during rest. This dysfunctional brain connectivity may contribute to decrease self-control, impaired inhibitory function as well deficits in stress regulation in chronic heroin users. 相似文献
97.
Heat shock proteins (Hsp) are highly conserved molecules, which are both constitutively expressed and up‐regulated in response to various stress conditions. In particular, fungal Hsp60 can act as immunodominant antigens and facilitate powerful immunological properties. A possible cellular heat shock response was investigated in eight fungi (Aspergillus fumigatus, Aspergillus terreus, Penicillium chrysogenum, Cladosporium cladosporioides, Scedosporium apiospermum, Trichophyton mentagrophytes, Candida albicans and Saccharomyces cerevisiae). Fully automated RNA extraction was followed by quantitative real‐time RT‐PCR targeting fungus‐specific Hsp60 mRNA and sequencing of the amplicon. Levels of temperature‐dependent gene expression were evaluated and rates of similarity and identity were compared. While Hsp60 mRNA was constitutively expressed in all the samples tested, a temperature‐dependent induction was not shown in C. cladosporioides. In the 80‐amino acid fragment from the hypothetical protein, 66% of the amino acids were identical, 20% showed a conserved and 8% a semi‐conserved substitution. Our findings should contribute to a better understanding of host–pathogen relationship and suggest that fungal Hsp60 under temperature‐related stress conditions might act as an immunogenic trigger in orchestrating fungi‐related diseases. 相似文献
98.
99.
用RP-HPLC指纹图谱控制复方丹参滴丸中低波长紫外吸收指纹成分 总被引:4,自引:3,他引:1
目的采用双定性双定量相似度作为评价指标,建立了复方丹参滴丸(CDDP)中低波长紫外吸收指纹成分的控制方法。方法采用RP-HPLC法以Century SIL C18BDS柱(200mm×4.6mm,5μm);以色谱指纹图谱指数F为目标函数优化选择指纹图谱检测条件,确定流动相为水-乙腈低压梯度洗脱,紫外检测波长:203nm,柱温:(30.00±0.15)℃,进样量:10μL。以双定性双定量相似度法对10批CDDP进行质量评价。结果以人参皂苷Rg1为参照物峰,确定18个共有指纹峰,建立了CDDP低波长紫外吸收指纹成分的HPLC指纹图谱。评价出10批CDDP的双定性双定量相似度均合格,表明此10批样品的低波长紫外吸收指纹成分的数量、分布比例和含量特征是十分相似的,表现出很好的质量均一性。结论本试验证明双定性双定量相似度法可有效控制CDDP中低波长紫外吸收指纹成分。 相似文献
100.
The relationship between bipartite ranking algorithms, graph theory and ROC analysis has been formerly established with data sampled from two categories (i.e. classes). In this article, we discuss extensions for more general ranking models, with data sampled from, in general, r ordered categories. Similarly, such models can be visualized by means of a layered ranking graph in which each path in the graph corresponds to an r-tuple of correctly ranked objects with one object of each class. From an ROC analysis point of view, the fraction of correctly ranked r-tuples equals the volume under the ROC surface (VUS) for r ordered categories. Unlike the conventional kernel approach of minimizing the pairwise error, we try to optimize the fraction of correctly ranked r-tuples. A large number of constraints appear in the resulting quadratic program, but the optimal solution can be computed in time for samples of size n with structured support vector machines and graph-based techniques. Our approach can offer benefits for applications in various domains. On various synthetic and benchmark data sets, it outperforms the pairwise approach for balanced as well as unbalanced problems. In addition, scaling experiments confirm the theoretically derived time complexity. 相似文献