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131.
Yajun Zheng Colin M. Tice Suresh B. Singh 《Bioorganic & medicinal chemistry letters》2017,27(13):2825-2837
In structure-based drug design, the basic goal is to design molecules that fit complementarily to a given binding pocket. Since such computationally modeled molecules may not adopt the intended bound conformation outside the binding pocket, one challenge is to ensure that the designed ligands adopt similar low energy conformations both inside and outside of the binding pocket. Computational chemistry methods and conformational preferences of small molecules from PDB and Cambridge Structural Database (CSD) can be used to predict the bound structures of the designed molecules. Herein, we review applications of conformational control in structure-based drug design using selected examples from the recent medicinal chemistry literature. The main purpose is to highlight some intriguing conformational features that can be applied to other drug discovery programs. 相似文献
132.
Primary photoprocesses of phytochrome. Picosecond fluorescence kinetics of oat and pea phytochromes 总被引:2,自引:0,他引:2
P S Song B R Singh N Tamai T Yamazaki I Yamazaki S Tokutomi M Furuya 《Biochemistry》1989,28(8):3265-3271
The primary photoprocesses of etiolated oat and pea phytochromes (Pr forms) are diffusion-modulated by the microscopic viscosity within the chromophore pocket. The chromophore pocket is preferentially accessible to glycerol but not to Ficoll. Glycerol preferentially retarded the rate (rate constant ca. 1-2 X 10(10) s-1) of the initial reaction from the Qy excited state of phytochrome, whereas it increased the long fluorescence lifetime (nanosecond) component that can be attributed to either an emitting intermediate or to modified/conformationally heterogeneous phytochrome populations. The picosecond time-resolved fluorescence spectra of different phytochrome preparations (i.e., full-length vs 6/10-kDa NH2-terminus truncated forms of phytochromes from monocot and dicot plants) revealed no significant differences. The spectra in the picosecond time scale showed no spectral shifts, but at longer time scales of up to approximately 1.90 ns, significant blue spectral shifts were observed. The shifts were more in the truncated than in the full-length pea phytochrome. Comparison of the fluorescence decay data and the picosecond time-resolved fluorescence spectra suggests differences in conformational flexibility/heterogeneity among the preparations of the monocot vs dicot phytochromes and the full-length native vs the amino terminus truncated phytochromes. 相似文献
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134.
The two primary objectives of this paper are: (a) to demonstrate how Comma, a business modeling methodology based on commitments, can be applied in healthcare process modeling, and (b) to evaluate the effectiveness of such an approach in producing healthcare process models. We apply the Comma approach on a breast cancer diagnosis process adapted from an HHS committee report, and presents the results of an empirical study that compares Comma with a traditional approach based on the HL7 Messaging Standard (Traditional-HL7). Our empirical study involved 47 subjects, and two phases. In the first phase, we partitioned the subjects into two approximately equal groups. We gave each group the same requirements based on a process scenario for breast cancer diagnosis. Members of one group first applied Traditional-HL7 and then Comma whereas members of the second group first applied Comma and then Traditional-HL7—each on the above-mentioned requirements. Thus, each subject produced two models, each model being a set of UML Sequence Diagrams. In the second phase, we repartitioned the subjects into two groups with approximately equal distributions from both original groups. We developed exemplar Traditional-HL7 and Comma models; we gave one repartitioned group our Traditional-HL7 model and the other repartitioned group our Comma model. We provided the same changed set of requirements to all subjects and asked them to modify the provided exemplar model to satisfy the new requirements. We assessed solutions produced by subjects in both phases with respect to measures of flexibility, time, difficulty, objective quality, and subjective quality. Our study found that Comma is superior to Traditional-HL7 in flexibility and objective quality as validated via Student’s t-test to the 10% level of significance. Comma is a promising new approach for modeling healthcare processes. Further gains could be made through improved tooling and enhanced training of modeling personnel. 相似文献
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137.
MOTIVATION: Comparative analysis of metabolic pathways in different genomes can give insights into the understanding of evolutionary and organizational relationships among species. This type of analysis allows one to measure the evolution of complete processes (with different functional roles) rather than the individual elements of a conventional analysis. We present a new technique for the phylogenetic analysis of metabolic pathways based on the topology of the underlying graphs. A distance measure between graphs is defined using the similarity between nodes of the graphs and the structural relationship between them. This distance measure is applied to the enzyme-enzyme relational graphs derived from metabolic pathways. Using this approach, pathways and group of pathways of different organisms are compared to each other and the resulting distance matrix is used to obtain a phylogenetic tree. RESULTS: We apply the method to the Citric Acid Cycle and the Glycolysis pathways of different groups of organisms, as well as to the Carbohydrate metabolic networks. Phylogenetic trees obtained from the experiments were close to existing phylogenies and revealed interesting relationships among organisms. 相似文献
138.
Tomkowicz B Singh SP Lai D Singh A Mahalingham S Joseph J Srivastava S Srinivasan A 《DNA and cell biology》2005,24(1):10-20
Human herpesvirus-8 (HHV-8) is causally linked to Kaposi's sarcoma (KS). Sequence analysis of the genome and subsequent studies revealed several genes including kaposin, with transformation properties in cell culture. In this study, we have analyzed the requirement of Kaposin A for cellular transformation in an effort to understand its contribution towards KS pathogenesis. Comparative analysis of Kaposin with other proteins identified the LXXLL motif spanning from residues 31-35 (LVCLL). The observation that the LXXLL motif is present in nuclear receptor coactivators that mediate the interaction of coactivators with nuclear receptors has prompted us to investigate the relevance of this motif for Kaposin's function(s). Kaposin A coding sequences were cloned into a eukaryotic expression plasmid with the Flag (FL) epitope fused in-frame at the C-terminus (Kap-FL). To evaluate the role of leucine residues in the motif, site-directed mutagenesis was utilized, whereby alanine was substituted for the leucine residues (Kap-AXXAA-FL). Both Kap-FL and Kap- AXXAA-FL exhibited similar levels of expression in cells. Interestingly, the Kap-AXXAA-FL mutant failed to show transforming activity by two independent assays: anchorage-independent growth, and focus formation. Immunofluorescence (IFA) and FACS analysis indicated that Kap-FL was localized around the nucleus and at the cell surface, respectively. However, Kap-AXXAA-FL exhibited diffuse cytoplasmic staining as measured by IFA yet was still detectable on the cell surface by FACS. Ironically, both Kap-FL and Kap-AXXAAFL were able to activate the AP-1 promoter. These results support an important role for the LXXLL motif in the ability of Kaposin to induce transformation. 相似文献
139.
Inderjeet Kaur Gurvinder Singh Kocher V. K. Gupta 《Indian journal of microbiology》2012,52(4):630-637
Bacillus circulans MTCC 7906, an extracellular alkaline protease producer was genetically characterized. B. circulans genomic DNA was isolated, oligonucleotide primers specific to alkaline protease gene of B. circulans were designed and its PCR amplification was done. The purified PCR product and pTrcHisA vector were subjected to restriction digestion with NcoI and HindIII and transformed into Escherichia coli DH5-α competent cells. The recombinant expression of alkaline protease gene studied by inducible expression and analysis by SDS-PAGE, established that the alkaline protease protein had an estimated molecular size of 46 kDa. Gene sequencing of the insert from selected recombinant clone showed it to be a 1329 bp gene encoding a protein of 442 amino acids. The sequence was blasted and aligned with known alkaline protease genes for comparison with their nucleotide and amino acid sequences. This identified major matches with three closely related subsp. of B. subtilis (B. subtilis subsp. subtilis strain 168, B. subtilis BSn5 and B. subtilis subsp. spizizenii strain W23). The insert also showed a number of substitutions (mutations) with other sp. of Bacillus which established that alkaline protease of B. circulans MTCC 7906 is a novel gene. The phylogenetic analysis of alkaline protease gene and its predicted amino acid sequences also validated that alkaline protease gene is a novel gene and the same has been accessioned in GenBank with accession number . JN645176.1相似文献
140.