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11.
Morais S Pandey PC Chen W Mulchandani A 《Chemical communications (Cambridge, England)》2003,(10):1188-1189
We report a novel method for screening and quantifying tubulin-binding antimitotic agents that promote microtubule formation. The method is based on the shift in the peak of the fluorescence emission difference spectrum of tubulin complexed to metal free tetrakis(4-carboxyphenyl)porphyrin (TCPP) in the presence of antimitotic agents. Taxol (paclitaxel), an anti-tumor drug approved for the treatment of a variety of cancers, caused the appearance of a new fluorescence peak at 645 nm at concentrations as low as 125 nM, the intensity of which was a function of the paclitaxel concentration. Cephalomannine caused the induction of a new fluorescence peak at 651 nm only above 1 muM. Baccatin did not induce the appearance of any new peak within detectable operating measurement conditions. These observations are in accordance with the biological activities/cytotoxicities of these compounds. Accordingly, it is proposed that the new method can be used for high throughput screening of antimitotic compounds. 相似文献
12.
Use of molecular dynamics in the design and structure determination of a photoinducible beta-hairpin
Kräutler V Aemissegger A Hünenberger PH Hilvert D Hansson T van Gunsteren WF 《Journal of the American Chemical Society》2005,127(13):4935-4942
The study presented here consists of three parts. In the first, the ability of a set of differently substituted diazobenzene-based linkers to act as photoswitchable beta-turn building blocks was assessed. A 12-residue peptide known to form beta-hairpins was taken as the basis for the modeling process. The central (beta-turn) residue pair was successively replaced by six symmetrically ((o,o), (m,m), or (p,p)) substituted (aminomethyl/carboxymethyl or aminoethyl/carboxyethyl) diazobenzene derivatives leading to a set of peptides with a photoswitchable backbone conformation. The folding behavior of each peptide was then investigated by performing molecular dynamics simulations in water (4 ns) and in methanol (10 ns) at room temperature. The simulations suggest that (o,o)- and (m,m)-substituted linkers with a single methylene spacer are significantly better suited to act as photoswitchable beta-turn building blocks than the other linkers examined in this study. The peptide containing the (m,m)-substituted linker was synthesized and characterized by NMR in its cis configuration. In the second part of this study, the structure of this peptide was refined using explicit-solvent simulations and NOE distance restraints, employing a variety of refinement protocols (instantaneous and time-averaged restraining as well as unrestrained simulations). We show that for this type of systems, even short simulations provide a significant improvement in our understanding of their structure if physically meaningful force fields are employed. In the third part, unrestrained explicit-solvent simulations starting from either the NMR model structure (75 ns) or a fully extended structure (25 ns) are shown to converge to a stable beta-hairpin. The resulting ensemble is in good agreement with experimental data, indicating successful structure prediction of the investigated hairpin by classical explicit-solvent molecular dynamics simulations. 相似文献
13.
Peng S Okeley NM Tsai AL Wu G Kulmacz RJ van der Donk WA 《Journal of the American Chemical Society》2002,124(36):10785-10796
Prostaglandin H synthase (PGHS) catalyzes the conversion of arachidonic acid to prostaglandin G(2) in the cyclooxygenase reaction. The first step of the mechanism has been proposed to involve abstraction of the pro-S hydrogen atom from C13 to generate a pentadienyl radical spanning C11-C15. We report here the synthesis of six site-specifically deuterated arachidonic acids to investigate the structure of the radical intermediate. The preparation of these compounds was achieved using a divergent scheme that involved one advanced intermediate for all targets. The synthetic design introduced the label late in the routes and allowed the utilization of common synthetic intermediates in the preparation of various targets. Both 13(R)- and 13(S)-deuterium-labeled arachidonic acids were synthesized in high enantiomeric purity as deduced from soybean lipoxygenase assays and mass spectrometric analysis of the resulting enzymatic products. Each synthetic compound was reacted under anaerobic conditions with the wide singlet tyrosyl radical of PGHS-2 to generate a radical intermediate that was analyzed by EPR. Deuterium substitution at positions 11, 13(S), and 15 resulted in the loss of one hyperfine interaction, indicating that the protons at these positions interact with the unpaired electron. Simulation of the spectra was achieved with one set of parameters that are consistent with the assignment of a pentadienyl radical. Use of 16-[(2)H(2)]-arachidonic acid indicated that only one of the protons at C16 gives rise to a strong hyperfine interaction. The findings are discussed in the context of two proposed mechanisms for the cyclooxygenase reaction. 相似文献
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Diastereoselective and enantioselective reduction of the β-ketoester by yeast to provided the chiral starting material for a synthesis of 4RS,6S,7S-serricornine, having the same configuration as the natural product. This material was converted into optically active and diastereomerically pure 6S,7S-anhydro-serricornine (). 相似文献
16.
Factor Xa is a serine protease which activates thrombin and plays a key regulatory role in the blood-coagulation cascade. Factor Xa is at the crossroads of the extrinsic and intrinsic pathways of coagulation and, hence, has become an important target for the design of anti-thrombotics (inhibitors). It is not known to be involved in other processes than hemostasis and its binding site is different to that of other serine proteases, thus facilitating selective inhibition. The design of high-affinity selective inhibitors of factor Xa requires knowledge of the structural and dynamical characteristics of its active site. The three-dimensional structure of factor Xa was resolved by X-ray crystallography and refined at 2.2 Å resolution by Padmanabhan and collaborators. In this article we present results from molecular dynamics simulations of the catalytic domain of factor Xa in aqueous solution. The simulations were performed to characterise the mobility and flexibility of the residues delimiting the unoccupied binding site of the enzyme, and to determine hydrogen bonding propensities (with protein and with solvent atoms) of those residues in the active site that could interact with a substrate or a potential inhibitor. The simulation data is aimed at facilitating the design of high-affinity selective inhibitors of factor Xa. 相似文献
17.
Riccardo Baron Daniel Trzesniak Alex H de Vries Andreas Elsener Siewert J Marrink Wilfred F van Gunsteren 《Chemphyschem》2007,8(3):452-461
Thermodynamic data are often used to calibrate or test amomic-level (AL) force fields for molecular dynamics (MD) simulations. In contrast, the majority of coarse-grained (CG) force fields do not rely extensively on thermodynamic quantities. Recently, a CG force field for lipids, hydrocarbons, ions, and water, in which approximately four non-hydrogen atoms are mapped onto one interaction site, has been proposed and applied to study various aspects of lipid systems. To date, no extensive investigation of its capability to describe salvation thermodynamics has been undertaken. In the present study, a detailed picture of vaporization, solvation, and phase-partitioning thermodynamics for liquid hydrocarbons and water was obtained at CG and AL resolutions, in order to compare the two types or models and evaluate their ability to describe thermodynamic properties in the temperature range between 263 and 343 K. Both CG and AL models capture the experimental dependence of the thermodynamic properties on the temperature, albeit a systematically weaker dependence is found for the CG model. Moreover, deviations are found for solvation thermodynamics and for the corresponding enthalpy-entropy compensation for the CG model. Particularly water/oil repulsion seems to be overestimated. However, the results suggest that the thermodynamic properties considered should be reproducible by a CG model provided it is reparametrized on the basis of these liquid-phase properties. 相似文献
18.
A stereospecific requirement for hallucinogenesis applies to certain molecules containing an asymmetric center. Thus, only the R-isomers of substituted phenylisopropylamines and lysergic acid diethylamide are psychotomimetic. The enantiomers of a minor hallucinogen, S(+)- and R(-)-3-(2-aminopropyl)indole (α-methyltryptamine) ( 6a and 6b ) were synthesized via a 5-step manipulation from D - and L -tryptophan ethyl ester hydrochloride, respectively. Optical purity of these two isomers was determined by pmr spectroscopy of their complexes with a europium chiral shift reagent using the indole C2 H signal. 相似文献
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