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5-Azidoisoxazoles are prepared via displacement of a chlorine atom in 5-chloroisoxazoles with azide ion. These 5-azidoisoxazoles contain an unsaturated group (olefin, aldehyde, oxime or hydrazone) in the 4-position which participates during thermal decomposition of the azide. Two types of products are formed which are non-interconvertible: (i) bicyclic isoxazoles which result from direct attack of the azide or nitrene on the unsaturated group; (ii) monocyclic pyrroles and pyrazoles which result from ring opening followed by bond reorganization and subsequent ring closure. Mechanisms for the two discrete processes are discussed. 相似文献
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By employing a modified protocol of the Molecular Mechanics with Poisson-Boltzmann Surface Area (MM-PBSA) methodology we substantially decrease the required computation time for calculating relative estimates of protein-ligand binding affinities. The modified method uses a generalized Born implicit solvation model during molecular dynamics to enhance conformational sampling as well as a very efficient Poisson-Boltzmann solver and a computational design based on a distributed-computing paradigm. This construction allows for reduction of the computational cost of the calculations by roughly 2 orders of magnitude compared to the traditional formulation of MM-PBSA. With this high-throughput version of MM-PBSA we show that one can produce efficient physics-based estimates of relative binding free energies with reasonable correlation to experimental data and a total computation time that is sufficiently low such that an industrially relevant throughput can be realized given currently accessible computing resources. We demonstrate this approach by performing a comparison of different MM-PBSA implementations on a set of 18 ligands for the protein target urokinase. 相似文献
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As molecular modellers we need to remember that the flexibility of a protein is necessary for it to function. Unfortunately,
this flexibility is not readily apparent from the seductive molecular graphics rendering of cryocrystallographic results. 相似文献
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We have developed a system for performing computations on an enterprise grid using a freely available package for grid computing that allows us to harvest unused CPU cycles off of employee desktop computers. By modifying the traditional formulation of Molecular Mechanics with Poisson-Boltzmann Surface Area (MM-PBSA) methodology, in combination with a coarse-grain parallelized implementation suitable for deployment onto our enterprise grid, we show that it is possible to produce rapid physics-based estimates of protein-ligand binding affinities that have good correlation to experimental data. This is demonstrated by examining the correlation of our calculated binding affinities to experimental data and also by comparison to the correlation obtained from the binding-affinity calculations using traditional MM-PBSA that are reported in the literature. 相似文献
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Stewart KD Steffy K Harris K Harlan JE Stoll VS Huth JR Walter KA Gramling-Evans E Mendoza RR Severin JM Richardson PL Barrett LW Matayoshi ED Swift KM Betz SF Muchmore SW Kempf DJ Molla A 《Journal of computer-aided molecular design》2007,21(1-3):121-130
Two new proteins of approximately 70 amino acids in length, corresponding to an unnaturally-linked N- and C-helix of the ectodomain
of the gp41 protein from the human immunodeficiency virus (HIV) type 1, were designed and characterized. A designed tripeptide
links the C-terminus of the C-helix with the N-terminus of the N-helix in a circular permutation so that the C-helix precedes
the N-helix in sequence. In addition to the artificial peptide linkage, the C-helix is truncated at its N-terminus to expose
a region of the N-helix known as the “Trp-Trp-Ile” binding pocket. Sedimentation, crystallographic, and nuclear magnetic resonance
studies confirmed that the protein had the desired trimeric structure with an unoccupied binding site. Spectroscopic and centrifugation
studies demonstrated that the engineered protein had ligand binding characteristics similar to previously reported constructs.
Unlike previous constructs which expose additional, shallow, non-conserved, and undesired binding pockets, only the single
deep and conserved Trp-Trp-Ile pocket is exposed in the proteins of this study. This engineered version of gp41 protein will
be potentially useful in research programs aimed at discovery of new drugs for therapy of HIV-infection in humans. 相似文献
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Methyl-methine linkages of Novolac, a commercially available t-butylphenol acetylene condensed (TBPA) resin, have been identified by recognition of pyrolysis pathways using pyrolysis-gas chromatography/mass spectrometry (Py-GC/mS) in vulcanized rubber. The diagnostic mass spectrum of t-butylphenol with methyl-methine linkages between phenolic rings was observed at m/z 192, corresponding to 4-t-butyl-2-ethyl-6-methylphenol. Other molecular ions were observed at m/z 178, 164, and 150 in the characteristic pyrolyzates. The ion at m/z 192 in the TBPA resin was observed to be characteristic for methyl-methine linkages between the phenolic groups, and the analytical pyrolysis-GC/mS method was thus able to identify the resin at low levels in vulcanized rubber. Copyright 1999 John Wiley & Sons, Ltd. 相似文献
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Muchmore SW Debe DA Metz JT Brown SP Martin YC Hajduk PJ 《Journal of chemical information and modeling》2008,48(5):941-948
A wide variety of computational algorithms have been developed that strive to capture the chemical similarity between two compounds for use in virtual screening and lead discovery. One limitation of such approaches is that, while a returned similarity value reflects the perceived degree of relatedness between any two compounds, there is no direct correlation between this value and the expectation or confidence that any two molecules will in fact be equally active. A lack of a common framework for interpretation of similarity measures also confounds the reliable fusion of information from different algorithms. Here, we present a probabilistic framework for interpreting similarity measures that directly correlates the similarity value to a quantitative expectation that two molecules will in fact be equipotent. The approach is based on extensive benchmarking of 10 different similarity methods (MACCS keys, Daylight fingerprints, maximum common subgraphs, rapid overlay of chemical structures (ROCS) shape similarity, and six connectivity-based fingerprints) against a database of more than 150,000 compounds with activity data against 23 protein targets. Given this unified and probabilistic framework for interpreting chemical similarity, principles derived from decision theory can then be applied to combine the evidence from different similarity measures in such a way that both capitalizes on the strengths of the individual approaches and maintains a quantitative estimate of the likelihood that any two molecules will exhibit similar biological activity. 相似文献