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We report a new structure-based strategy for the identification of novel inhibitors. This approach has been applied to Bacillus stearothermophilus alanine racemase (AlaR), an enzyme implicated in the biosynthesis of the bacterial cell wall. The enzyme catalyzes the racemization of l- and d-alanine using pyridoxal 5-phosphate (PLP) as a cofactor. The restriction of AlaR to bacteria and some fungi and the absolute requirement for d-alanine in peptidoglycan biosynthesis make alanine racemase a suitable target for drug design. Unfortunately, known inhibitors of alanine racemase are not specific and inhibit the activity of other PLP-dependent enzymes, leading to neurological and other side effects.This article describes the development of a receptor-based pharmacophore model for AlaR, taking into account receptor flexibility (i.e. a `dynamic' pharmacophore model). In order to accomplish this, molecular dynamics (MD) simulations were performed on the full AlaR dimer from Bacillus stearothermophilus (PDB entry, 1sft) with a d-alanine molecule in one active site and the non-covalent inhibitor, propionate, in the second active site of this homodimer. The basic strategy followed in this study was to utilize conformations of the protein obtained during MD simulations to generate a dynamic pharmacophore model using the property mapping capability of the LigBuilder program. Compounds from the Available Chemicals Directory that fit the pharmacophore model were identified and have been submitted for experimental testing.The approach described here can be used as a valuable tool for the design of novel inhibitors of other biomolecular targets. 相似文献
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Ioan Bicu Fanica Mustata 《Journal of polymer science. Part A, Polymer chemistry》2005,43(24):6308-6322
The Diels–Alder adduct of levopimaric acid with acrylonitrile was efficiently prepared from resin acids. Excellent addition reaction yields (ca. 95%) were obtained. The adduct was converted into polyamides by polycondensation with diamines. When the same adduct was subjected to a dehydrodecarboxylation reaction, a novel ketone dinitrile derivative was obtained. This trifunctional product was also converted into polyamides by polycondensation with diamines. When the ketone dinitrile was hydrolyzed in the presence of alkalies and the reaction product was chlorinated, a ketone diacid chloride was obtained. A polyester was synthesized by the polycondensation of the diacid chloride with a diol. The structures of the Diels–Alder adduct, ketone dinitrile derivative, ketone diacid chloride, and polymers were established by means of elemental analysis, IR and NMR spectroscopy, and molecular weight determinations. Both the polyamides and the polyester were low‐molecular‐weight polymers soluble in polar solvents. The thermal behavior of the monomers and polymers was evaluated by thermogravimetric analysis. The thermal studies showed that the polymers were fairly thermostable substances, except the polyester, which appeared to be a substance with good thermal stability. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 6308–6322, 2005 相似文献
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R. Mustata R.J. Hayhurst D.R. Hayhurst F. Vakili-Tahami 《Archive of Applied Mechanics (Ingenieur Archiv)》2006,75(8-9):475-495
The paper reports the use of three-dimensional creep continuum damage mechanics techniques to study the creep failure of a
medium-bore low-alloy ferritic-steel cylinder–cylinder branched pressure vessel welded connection, tested at a constant pressure
of 4 MPa, at a uniform temperature of 590°C. The development of computational techniques is reported to analyse this problem
with a four-material model of the welded connection which includes: parent, type IV, heat-affected zone (HAZ) and weld materials.
The results of analyses are presented for two sets of creep damage constitutive equations. For both equation sets, lifetimes
are conservatively, yet accurately predicted; however, the results of metallographic examinations of a tested vessel are not
accurately predicted. To overcome this deficiency further analyses of the vessel are recommended which include: a coarse-grained
HAZ (CGHAZ), adjacent to the weld material; and, more-refined finite element modelling. 相似文献
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The possibility to build a high power copper laser using a new type of discharge – heated cathode discharge in the copper vapours continuously evaporated from a melted spot on the anode surface is analysed. From the experimental data on this new discharge type, the equivalent pressure of the copper atoms in the discharge space has been obtained. This pressure can be as high as 1 torr. The density of the power in the discharge volume is evaluated to be more than 1 kW/cm3. 相似文献
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Synthesis of maleated pimaric acid (MPA) cellulose esters is first reported in this work. Cellulose esterification was performed by reacting microcrystalline cellulose with monoacid chloride of MPA (MPA-Cl) in presence of pyridine as catalyst and reaction medium. The syntheses were started in a heterogeneous solid–liquid reaction medium, but as the reaction advanced, the reaction mass turned into a homogeneous solution. The effects of MPA-Cl/anhydroglucose unit molar ratio, reaction temperature, and reaction duration on the yield and degree of substitution (DS) of cellulose esters (CEs) were investigated. CEs with DS ranging from 2.6 to 2.8 were achieved at molar ratios of 5.5–6.0 after 12–16 h at 118 °C. The purified products were characterized by elemental analysis, IR and 13C-NMR spectroscopy, and thermogravimetric analysis. CEs are soluble or partially soluble in usual organic solvents, depending on DS. Transparent films were prepared using CE-cyclohexanone solutions. 相似文献
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V. Kuncser M. Valeanu G. Schinteie G. Filoti I. Mustata C.P. Lungu A. Anghel H. Chiriac R. Vladoiu J. Bartolome 《Journal of magnetism and magnetic materials》2008,320(14):e226-e230
Exchange bias and spin valve systems with Fe–Mn antiferromagnetic layers of different Fe concentrations were obtained by the thermo-ionic vacuum arc method. The adherence of the multilayer system to the Si substrate depends on the Fe–Mn composition. The overall roughness depends on the growing order of the antiferromagnetic/ferromagnetic layers. Very low blocking temperatures for exchange bias were observed for the considered compositions of the Fe–Mn layer. The coercive forces of both the pinned and the free layers of spin valve structures can be considerably modified along a large set of samples simultaneously prepared. 相似文献
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V. Kuncser G. Schinteie P. Palade I. Mustata C. P. Lungu N. Stefan H. Chiriac R. Vladoiu G. Filoti 《Hyperfine Interactions》2009,191(1-3):135-141
Exchange bias and spin valve structures with Fe as ferromagnetic layers selectively enriched in 57Fe and Ir–Mn of different compositions as antiferromagnetic pinning layers have been prepared by r.f. sputtering. Conversion Electron Mössbauer Spectroscopy and Magneto Optic Kerr Effect have shown that the local structure and interactions in the whole ferromagnetic layers, with direct influence on their magnetic reversal processes, depend on growing order of the layers and composition of the AF layer. Interfacial atomic diffusion is the main reason of perturbing the local structure of the ferromagnet. Mössbauer Spectroscopy is a powerfool tool which allows a detailed analysis of local configurations, in order to optimize the magnetic and giant magnetoresistive parameters of such multilayers of important technological applications. 相似文献
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Mircea Mustata 《Transactions of the American Mathematical Society》2006,358(11):5015-5023
In this note we compute multiplier ideals of hyperplane arrangements. This is done using the interpretation of multiplier ideals in terms of spaces of arcs by Ein, Lazarsfeld, and Mustata (2004).
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