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NMR Data (nmr + data)
Selected AbstractsNovel Phthalocyaninatobis(alkylcarboxylato)silicon(IV) Compounds: NMR Data and X-ray Structures To Study the Spacing Provided by Long Hydrocarbon Tails That Enhance Their SolubilityCHEMISTRY - A EUROPEAN JOURNAL, Issue 14 2005Jose L. Sosa-Sánchez Dr. Abstract The reaction between trans -PcSiCl2 (1) and the potassium salts of six fatty acids (2,a,2,f) led to the trans -PcSi[OOC(CH2)nCH3]2 compounds (3,a,3,f), which were characterised by elemental analysis, IR, UV/Vis and 1H, 13C, and 29Si NMR spectroscopy. From a detailed study of the NMR spectra, the strong anisotropic currents of the Pc macrocycle were found to have an effect on up to the sixth methylenic group. As expected, the length of the hydrocarbon tail does not affect the chemical shift of the 29Si nucleus of any of the compounds, appearing at around ,222.6. The structures of PcSi[OOC(CH2)nCH3]2, where n=7, 10, 12, 13 and 20, were determined by X-ray crystallography. All the compounds were found to be triclinic with a P space group. In all cases the observed crystallographic pseudosymmetry is Ci and the asymmetric unit consists of half a molecule. The silicon atom is at the centre of a distorted octahedron and hence its coordination number is six. The carboxylate fragments are in a trans configuration with respect to the Pc macrocycle. The supramolecular structures are discussed in detail herein. The correlation between the 1H NMR chemical shifts and the position of the corresponding carbon atoms in the hydrocarbon tail reveals that the dicarboxylate substituents exhibit a spacer-like behaviour that enhances the solubility. A detailed study of the tail variable allowed us to evaluate the loss of radial shielding along the Pc2, ligand. [source] Calculated on 1H and 13C NMR chemical shifts of 2,4-difluorobenzaldehyde isonicotinoylhydrazone and 2,3-dichlorobenzaldehyde isonicotinoylhydrazone with GIAO, IGAIM, and CSGT modelsCONCEPTS IN MAGNETIC RESONANCE, Issue 5 2009N. Günay Abstract The 1H and 13C NMR chemical shifts of the 2,4-difluorobenzaldehyde isonicotinoylhydrazone (I) and 2,3-dichlorobenzaldehyde isonicotinoylhydrazone (II) were determined with the help of full spectral analysis. The geometry and electronic structure of the title compounds were investigated at both the ab initio Hartree-Fock and the B3LYP levels with 6-31+G(d,p) basis set. The NMR data were calculated by means of the GIAO, CSGT, and IGAIM methods. All quantum-chemical calculations, including those of NMR data, were performed by ab initio level HF and DFT methods. Excellent agreement between the theoretical and experimental results was found for the HF level 1H and 13C chemical shifts. The parameters of molecular geometry and 1H and 13C chemical shift values of the title compounds (I, II) in the ground state have been calculated and and compared with corresponding experimental result. © 2009 Wiley Periodicals, Inc. Concepts Magn Reson Part A 34A: 297,304, 2009. [source] The embedded ion method: A new approach to the electrostatic description of crystal lattice effects in chemical shielding calculationsCONCEPTS IN MAGNETIC RESONANCE, Issue 5 2006Dirk Stueber Abstract The nuclear magnetic shielding anisotropy of NMR active nuclei is highly sensitive to the nuclear electronic environment. Hence, measurements of the nuclear magnetic shielding anisotropy represent a powerful tool in the elucidation of molecular structure for a wide variety of materials. Quantum mechanical ab initio nuclear magnetic shielding calculations effectively complement the experimental NMR data by revealing additional structural information. The accuracy and capacity of these calculations has been improved considerably in recent years. However, the inherent problem of the limitation in the size of the systems that may be studied due to the relatively demanding computational requirements largely remains. Accordingly, ab initio shielding calculations have been performed predominantly on isolated molecules, neglecting the molecular environment. This approach is sufficient for neutral nonpolar systems, but leads to serious errors in the shielding calculations on polar and ionic systems. Conducting ab initio shielding calculations on clusters of molecules (i.e., including the nearest neighbor interactions) has improved the accuracy of the calculations in many cases. Other methods of simulating crystal lattice effects in shielding calculations that have been developed include the electrostatic representation of the crystal lattice using point charge arrays, full ab initio methods, ab initio methods under periodic boundary conditions, and hybrid ab initio/molecular dynamics methods. The embedded ion method (EIM) discussed here follows the electrostatic approach. The method mimics the intermolecular and interionic interactions experienced by a subject molecule or cluster in a given crystal in quantum mechanical shielding calculations with a large finite, periodic, and self-consistent array of point charges. The point charge arrays in the EIM are generated using the Ewald summation method and embed the molecule or ion of interest for which the ab initio shielding calculations are performed. The accuracy with which the EIM reproduces experimental nuclear magnetic shift tensor principal values, the sensitivity of the EIM to the parameters defining the point charge arrays, as well as the strengths and limitations of the EIM in comparison with other methods that include crystal lattice effects in chemical shielding calculations, are presented. © 2006 Wiley Periodicals, Inc. Concepts Magn Reson Part A 28A: 347,368, 2006 [source] Molecular recognition of sugars by lanthanide (III) complexes of a conjugate of N, N -bis[2-[bis[2-(1, 1-dimethylethoxy)-2-oxoethyl]amino]ethyl]glycine and phenylboronic acidCONTRAST MEDIA & MOLECULAR IMAGING, Issue 4 2007Elisa Battistini Abstract A novel conjugate of phenylboronic acid and an Ln(DTPA) derivative, in which the central acetate pendant arm was replaced by the methylamide of L -lysine, was synthesized and characterized. The results of a fit of variable 17O NMR data and a 1H NMRD profile show that the water residence lifetime of the Gd(III) complex (150,ns) is shorter than that of the parent compound Gd(DTPA)2, (303,ns). Furthermore, the data suggest that several water molecules in the second coordination sphere of Gd(III) contribute to the relaxivity of the conjugate. The Ln(III) complexes of this conjugate are highly suitable for molecular recognition of sugars. The interaction with various sugars was investigated by 11B NMR spectroscopy. Thanks to the thiourea function that links the phenylboronic acid targeting vector with the DTPA derivative, the interactions are stronger than that of phenylboronic acid itself. In particular, the interaction with N -propylfructosamine, a model for the glucose residue in glycated human serum albumin (HSA), is very strong. Unfortunately, the complex also shows a rather strong interaction with hexose-free HSA (KA,=,705,±,300). Copyright © 2007 John Wiley & Sons, Ltd. [source] Novel 1,2-Dicarba- closo -dodecaborane(12) Derivatives of SeleniumEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 2 2007Bernd Wrackmeyer Abstract Lithiation of 1,2-dicarba- closo -dodecaborane(12) (1) followed by insertion of selenium into both C,Li bonds leads to the 1,2-diselenolato-1,2-dicarba- closo -dodecaborane(12) dianion (3), which is converted by oxidative coupling into the cyclic eight-membered bis(diselane) 4 with annellated carborane moieties. Oxidative addition of 4 to ethenebis(triphenylphosphane)platinum(0) gives the bis(triphenylphosphane)platinum(II) complex 7, which contains a chelating 1,2-diselenolato-1,2-dicarba- closo -dodecaborane(12) ligand, by symmetric cleavage of the eight-membered ring in 4 and displacement of ethene. The molecular structures of 4 and 7 were determined by X-ray analysis. The solution-state structures of the new compounds are supported by multinuclear NMR data (1H, 11B, 13C, 29Si, 31P, 77Se, 195Pt). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Molecular dynamics simulations of solvated UDP,glucose in interaction with Mg2+ cationsFEBS JOURNAL, Issue 20 2001Pavla Petrová ,Glycosyltransferases are key enzymes involved in biosynthesis of oligosaccharides. Nucleotide-sugars, the glycosyltransferase substrates, serve as activated donors of sugar residues during the enzymatic reaction Although very little is known about the catalytic mechanism of these enzymes, it appears that the catalytic activity in most glycosyltransferases is dependent upon the presence of a divalent cation, for example Mn2+ or Mg2+. It is not known whether the ion is bound to the enzyme before its interaction with the substrate, or if it binds the substrate before the enzymatic reaction to modify its conformation to fit better the active site of the enzyme. We have inspected the latter possibility by running four 2-ns molecular dynamics trajectories on fully solvated UDP-glucose in the presence of Mg2+ ions. Our results indicate that the divalent cation interacts strongly with the nucleotide-sugar in solution, and that it can alter its conformational behavior. It is also shown that a conformation of the pyrophosphate moiety that results in an eclipsed or almost eclipsed orientation of two of the oxygen atoms, and which is found in protein interacting with a nucleotide di- or tri-phosphate X-ray data, is energetically favored. The results are also discussed in light of existing NMR data, and are found to be in a good agreement with them. [source] Three-dimensional structure of the histidine-containing phosphocarrier protein (HPr) from Enterococcus faecalis in solutionFEBS JOURNAL, Issue 3 2001Till Maurer The histidine-containing phosphocarrier protein (HPr) transfers a phosphate group between components of the prokaryotic phosphoenolpyruvate-dependent phosphotransferase system (PTS), which is finally used to phosphorylate the carbohydrate transported by the PTS through the cell membrane. Recently it has also been found to act as an intermediate in the signaling cascade that regulates transcription of genes related to the carbohydrate-response system. Both functions involve phosphorylation/dephosphorylation reactions, but at different sites. Using multidimensional 1H-NMR spectroscopy and angular space simulated annealing calculations, we determined the structure of HPr from Enterococcus faecalis in aqueous solution using 1469 distance and 44 angle constraints derived from homonuclear NMR data. It has a similar overall fold to that found in HPrs from other organisms. Four , strands, A, B, C, D, encompassing residues 2,7, 32,37, 40,42 and 60,66, form an antiparallel , sheet lying opposite the two antiparallel , helices, a and c (residues 16,26 and 70,83). A short , helix, b, from residues 47,53 is also observed. The pairwise root mean square displacement for the backbone heavy atoms of the mean of the 16 NMR structures to the crystal structure is 0.164 nm. In contrast with the crystalline state, in which a torsion angle strain in the active-center loop has been described [Jia, Z., Vandonselaar, M., Quail, J.W. & Delbaere, L.T.J. (1993) Nature (London) 361, 94,97], in the solution structure, the active-site His15 rests on top of helix a, and the phosphorylation site N,1 of the histidine ring is oriented towards the surface, making it easily accessible to the solvent. Back calculation of the 2D NOESY NMR spectra from both the NMR and X-ray structures shows that the active-center structure derived by X-ray crystallography is not compatible with experimental data recorded in solution. The observed torsional strain must either be a crystallization artefact or represents a conformational state that exists only to a small extent in solution. [source] Molecular mechanism of ubiquitin recognition by GGA3 GAT domainGENES TO CELLS, Issue 7 2005Masato Kawasaki GGA (Golgi-localizing, ,-adaptin ear domain homology, ARF-binding) proteins, which constitute a family of clathrin coat adaptor proteins, have recently been shown to be involved in the ubiquitin-dependent sorting of receptors, through the interaction between the C-terminal three-helix-bundle of the GAT (GGA and Tom1) domain (C-GAT) and ubiquitin. We report here the crystal structure of human GGA3 C-GAT in complex with ubiquitin. A hydrophobic patch on C-GAT helices ,1 and ,2 forms a binding site for the hydrophobic Ile44 surface of ubiquitin. Two distinct orientations of ubiquitin Arg42 determine the shape and the charge distribution of ubiquitin Ile44 surface, leading to two different binding modes. Biochemical and NMR data strongly suggest another hydrophobic binding site on C-GAT helices ,2 and ,3, opposite to the first binding site, also binds ubiquitin although weakly. The double-sided ubiquitin binding provides the GAT domain with higher efficiency in recognizing ubiquitinated receptors for lysosomal receptor degradation. [source] Three New Limonoids from the Leaves of Cipadessa cinerascensHELVETICA CHIMICA ACTA, Issue 4 2010Zhi-Guo Zhang Abstract Three new limonoids, cipadesins G,I (1,3), together with four known ones, were isolated from the leaves of Cipadessa cinerascens. Their structures were elucidated on the basis of 1D- and 2D-NMR data. [source] New Epoxy-Substituted Nitrogenous Bisabolene-Type Sesquiterpenes from a Hainan Sponge Axinyssa sp.HELVETICA CHIMICA ACTA, Issue 3 2010Ji-Zheng Sun Abstract Two new uncommon epoxy-substituted nitrogenous bisabolene-type sesquiterpenes, 3-formamido-7,8-epoxy- , -bisabolane (4), 3-isocyano-7,8-epoxy- , -bisabolane (5), together with three known related sesquiterpenes, 1,3, were isolated from the Hainan sponge Axinyssa sp. Their structures were determined on the basis of extensive spectroscopic analyses and by comparison of their NMR data with those of structurally related compounds. [source] Comparison of DNA Complex Formation Behaviour for Two Closely Related Lexitropsin AnaloguesHELVETICA CHIMICA ACTA, Issue 5 2009Abstract Two closely related lexitropsin analogues that differ only in the form of the ,headgroup' functionality (CHO (for 1) vs. Ac (for 2)) have been studied in their DNA-binding capacity for the sequence d(GCATATATGC) using 1H-NMR spectroscopy. DNA-Complex formation for the CHO derivative was apparent from the observation of new NMR signals on titration of DNA with ligand. Detailed investigation and assignment of the data for a ligand/DNA-duplex ratio of 2,:,1 clearly delineated the structure as one associated with the ,minor groove' class of DNA complexes. The structure of the complex was determined on the basis of the acquired NMR data. Features characteristic of typical 2,:,1 minor-groove complexes were apparent. In a similar experimental approach, the Ac analogue ligand,DNA binding response was investigated. Despite the close similarity in chemical structure to the CHO case, the Ac analogue was found to produce NMR data of a much poorer quality. This was attributed to more rapid on/off chemical exchange equilibrium between ligand and DNA. From close analysis and comparison of the NMR data for the ,Ac' and ,CHO' headgroup ligand,DNA complexes, it was possible to ascertain that the same type of complex formed in each case but with different relative binding constants. Consideration of the nature and form of these complexes has been made with reference to a previously determined structure from our laboratory for the related lexitropsin analogue thiazotropsin A. [source] ,N-Stereogenic Quaternary Ammonium Salts' from L -Amino Acids: Synthesis, Separation, and Absolute ConfigurationHELVETICA CHIMICA ACTA, Issue 4 2009Hua-Fang Wu Abstract Diastereoisomeric linear and cyclic ,N-chiral quaternary ammonium salts' (QASs) were efficiently synthesized from corresponding L -amino acids in high yields. The diastereoisomers of each pair of ,N-chiral QASs' were successfully separated. The absolute configurations of these QASs were determined predominately by X-ray single-crystal analysis. The 1H-NMR data of ,N-chiral QASs' provided characteristic information on the configuration of the N-chiral center. ,N-Chiral QASs' exemplified by [N(R)]- 2a and [N(S)]- 2a are stable in protic and aprotic solvents within a broad pH and temperature range. [source] Pyrrolizidine Alkaloids and Bisabolane Sesquiterpenes from the Roots of Ligularia cymbuliferaHELVETICA CHIMICA ACTA, Issue 2 2008Chun-Mei Liu Abstract The new pyrrolizidine alkaloid glycoside 1, and the three new highly oxygenated bisabolane sesquiterpenes 4,6, together with the two known pyrrolizidine alkaloids 2 and 3, were isolated from the roots of Ligularia cymbulifera (W.,W. Smith) Hand.- Mazz. Their structures were established on the basis of spectroscopic analysis, especially 1D- and 2D-NMR data. The cytotoxic activities of compounds 1, 2, and 4,6 were evaluated against hepatoma (BEL-7402), human leukemia (HL-60), human ovarian carcinoma (HO-8910), and nasopharyngeal carcinoma (KB) cell lines (Tables 1,3). Compound 6 showed weak cell-growth inhibition of BEL-7402 cell. [source] New Eremophilenolactones from Senecio nemorensisHELVETICA CHIMICA ACTA, Issue 11 2007Fan-Jun Meng Abstract Three new eremophilane sesquiterpenes were isolated from the MeOH extract of the roots of Senecio nemorensis. Their structures were identified as 8, -hydroxy-6, -(isobutanoyloxy)-1-oxoeremophila-7(11),9-dieno-12,8, -lactone (1), 6,,8, -dimethoxy-1-oxoeremophila-7(11),9-dieno-12,8, -lactone (2), and 10, -hydroxy-6, -(isobutanoyloxy)-1-oxoeremophila-7(11),8-dieno-12,8-lactone (3), respectively, based on spectroscopic data, including IR, EI-MS, HR-ESI-MS, and 1D- and 2D-NMR data. [source] Triterpene Esters Isolated from Leaves of Maytenus salicifoliaReissekHELVETICA CHIMICA ACTA, Issue 4 2007Miranda, Rodrigues, Roqueline, Silva de Abstract The triterpene ester (3,)-olean-18-en-3-yl stearate (1), together with (3,)-urs-12-en-3-yl stearate (2), and (3,)-lup-20(29)-en-3-yl stearate (3) were isolated from leaves of Maytenus salicifoliaReissek (Celastraceae). The structure of 1, a new compound, including its configuration, was established by 1H, 13C, and DEPT-135 NMR data, including 2D experiments (HSQC, HMBC, COSY, and NOESY). The molecular mass (692 Da) was confirmed by gas chromatography coupled with mass spectrometry (CG/MS). [source] A Pair of New Nortriterpene Saponin Epimers from the Roots of Gypsophila oldhamianaHELVETICA CHIMICA ACTA, Issue 5 2006Jian-Guang Luo Abstract A pair of new oleanane-type nortriterpene saponin epimers, neogypsoside,A (1) and B (2) (Fig.,1) with neogypsogenin,A (3) and neogypsogenin,B (4) as the two new aglycons, as well as the two known triterpene saponins 5 and 6(Fig.,1), were isolated from the roots of Gypsophila oldhamiana. Their structures were determined by analysis of their NMR data. A possible biogenetic pathway to the nortriterpene saponins 1 and 2 is proposed (Scheme,2). [source] New Briaranes from the South China Sea Gorgonian Junceella fragilisHELVETICA CHIMICA ACTA, Issue 8 2005Shu-Hua Qi Three new briarane diterpenes, junceellonoids C,E (1,3), along with six known briaranes, junceellin A (4), praelolide (5), and junceellolides A-D (6,9), were isolated from the EtOH/CH2Cl2 extracts of the South China Sea gorgonian coral Junceella fragilis. The structures of 1,3 were established by extensive spectroscopic analysis, including 1D- and 2D-NMR data. Compounds 1 and 2 exhibited mild cytotoxicity against human galactophore carcinoma (MDA-mB-231 and MCF-7) cells at the concentration of 100,,M. [source] NMR Conformational Analysis and Theoretical Calculations for 2-Aryl- 1,3-dihydroxy-4,4,5,5-tetramethylimidazolidinesHELVETICA CHIMICA ACTA, Issue 2 2004Antônio Conformational studies of 1,3-dihydroxy-4,4,5,5-tetramethyl-2-(pyridin-1-yl)imidazolidine (1a) and 1,3-dihydroxy-4,4,5,5-tetramethyl-2-(pyridin-3-yl)imidazolidine (1b), carried out by using 1D 1H- and 13C-NMR and 2D HMQC, HMBC, and NOESY experiments and with the aid of theoretical calculations, indicate that the OH groups are trans to the pyridinyl substituent. Because the two 1H-NMR signals of the Me groups are distinguishable and do not change between 290 and 380,K, it is proposed that 1a and 1b have each only one conformation in this temperature range. This behavior was not found with 1,3-dihydroxy-4,4,5,5-tetramethyl-2-(pyridin-2-yl)imidazolidine (1c) because its Me 1H-NMR signals cross over at 300,K. Hence, more than one conformation must be present, beyond those produced by simple inversions. Theoretical calculations including temperature and solvent effects were performed to provide further information on the conformational analysis and to help to assign the NMR data. The combination of NMR measurements and quantum-chemical calculations is shown to be a very promising strategy for conformational analysis studies in solution. [source] Cyclopeptides and Amides from Pseudostellaria heterophylla (Caryophyllaceae)HELVETICA CHIMICA ACTA, Issue 10 2003Ya-bin Yang From the roots of Pseudostellaria heterophylla, three cyclopeptides and three amides were isolated, besides heterophyllin A and B. Their structures were determined as cyclo (Ala-Gly-Pro-Val-Tyr-) (heterophyllin J; 1), cyclo (Ala-Gly-Pro-Tyr-Leu-) (pseudostellarin A; 2), cyclo (Gly-Gly-Gly-Pro-Pro-Phe-Gly-Ile-) (pseudostellarin B; 3), methyl , -hydroxypyroglutamate (4), methyl pyroglutamate (5), and pyroglutamic acid (6) on the basis of spectral data, especially 2D-NMR data. Among them, compounds 1 and 4 are new compounds. [source] The first general synthesis of 3-iodo-4- R -furazansHETEROATOM CHEMISTRY, Issue 3 2004Aleksei B. Sheremetev The first general synthetic route has been developed for the convenient preparation of iodofurazans. The approach was accomplished by one-pot diazotization-iodation reaction of appropriate aminofurazans. A combination of sodium nitrite and iodine in organic solvent under anhydrous conditions as the reaction conditions allowed to solve problem in iodofurazans preparation. The investigation of the substituent's influence on NMR data of the iodofurazans has been carried out. The X-ray crystal structure of the 3-amino-4-iodofurazan 1d is reported. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:199,207, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20007 [source] Rationalization of the stereochemistry of an addition of dialkyl phosphites to certain chiral aldimines: The experimental and theoretical approachHETEROATOM CHEMISTRY, Issue 2 2002Ryszard B. Nazarski The absolute configuration of an ,-P stereogenic center in two diastereomeric O,O-dialkyl ,-aminophosphonates (3), arising from an induced 1,3-asymmetric phosphite addition to the CN bond of furfural-derived Schiff bases (1), was established from single product 1H NMR data. Such spectra were interpreted with anisotropic shielding in relation to the AM1 and MNDO/d structures of 3; the former ones turned out to be closer to the obtained experimental results (1H NMR spectra of 3, crystallographic database study). Since favored 3-21G geometries of starting imines 1 were modeled as well, it was inferred that a stereochemical outcome of this reaction is governed by Cram selectivity. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:120,125, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10005 [source] Synthesis and properties of organic/inorganic hybrid nanoparticles prepared using atom transfer radical polymerizationJOURNAL OF APPLIED POLYMER SCIENCE, Issue 5 2008Tzong-Liu Wang Abstract The synthesis of organic/inorganic hybrid materials was conducted by atom transfer radical polymerization (ATRP) of styrene and methyl methacrylate (MMA) from the surface of silica colloids. Colloidal initiators were prepared by the functionalization of silica nanoparticles with (3-(2-bromoisobutyryl)propyl) dimethylethoxysilane (BIDS). Well-defined polymer chains were grown from the nanoparticle surfaces to yield individual particles composed of a silica core and a well-defined outer polystyrene (PS) or poly(methyl methacrylate) (PMMA) layer. Fourier transform infrared (FTIR) and solid state 13C and 29Si-NMR spectroscopy confirmed the successful modification of nanosilica surfaces. Subsequent grafting of polymers on silica surfaces by ATRP was also performed with success based on FTIR and NMR data. Scanning electron microscopy (SEM) and silicon mapping showed both hybrid materials were homogeneous dispersion systems. Energy dispersive X-ray spectrometer (EDS) analysis indicated that the BIDS initiator was covalently attached on surfaces of silica nanoparticles and ATRP of styrene and MMA were accomplished. Thermogravimetric analysis (TGA) results displayed higher thermal stabilities for both nanohybrids in comparison with the linear-type vinyl polymers. Contact angle measurements revealed the nanomaterials character for both silica-based hybrid materials. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008 [source] Object-oriented approach to drug design enabled by NMR SOLVE: First real-time structural tool for characterizing protein,ligand interactionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue S37 2001Daniel S. Sem Abstract As a result of genomics efforts, the number of protein drug targets is expected to increase by an order of magnitude. Functional genomics efforts are identifying these targets, while structural genomics efforts are determining structures for many of them. However, there is a significant gap in going from structural information for a protein target to a high affinity (Kd,<,100 nM) inhibitor, and the problem is multiplied by the sheer number of new targets now available. nature frequently designs proteins in classes that are related by the reuse, through gene duplication events, of cofactor binding domains. This reuse of functional domains is an efficient way to build related proteins in that it is object-oriented. There is a growing realization that the most efficient drug design strategies for attacking the mass of targets coming from genomics efforts will be systems-based approaches that attack groups of related proteins in parallel. We propose that the most effective drug design strategy will be one that parallels the object-oriented manner by which nature designed the gene families themselves. IOPE (Integrated Object-Oriented PharmacoEngineering) is such an approach. It is a three-step technology to build focused combinatorial libraries of potential inhibitors for major families and sub-families of enzymes, using cogent NMR data derived from representatives of these protein families. The NMR SOLVE (Structurally Oriented Library Valency Engineering) data used to design these libraries are gathered in days, and data can be obtained for large proteins (>,170 kDa). Furthermore, the process is fully object-oriented in that once a given bi-ligand is identified for a target, potency is retained if different cofactor mimics are swapped. This gives the drug design process maximum flexibility, allowing for the more facile transition from in vitro potency to in vivo efficacy. J. Cell. Biochem. Suppl. 37: 99,105, 2001. © 2002 Wiley-Liss, Inc. [source] An improved nucleic acid parameter set for the GROMOS force fieldJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 7 2005Thereza A. Soares Abstract Over the past decades, the GROMOS force field for biomolecular simulation has primarily been developed for performing molecular dynamics (MD) simulations of polypeptides and, to a lesser extent, sugars. When applied to DNA, the 43A1 and 45A3 parameter sets of the years 1996 and 2001 produced rather flexible double-helical structures, in which the Watson,Crick hydrogen-bonding content was more limited than expected. To improve on the currently available parameter sets, the nucleotide backbone torsional-angle parameters and the charge distribution of the nucleotide bases are reconsidered based on quantum-chemical data. The new 45A4 parameter set resulting from this refinement appears to perform well in terms of reproducing solution NMR data and canonical hydrogen bonding. The deviation between simulated and experimental observables is now of the same order of magnitude as the uncertainty in the experimental values themselves. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 725,737, 2005 [source] Semiautomatic sequence-specific assignment of proteins based on the tertiary structure,The program st2nmrJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 3 2002Primo, Pristov Abstract The sequence-specific assignment of resonances is still the most time-consuming procedure that is necessary as the first step in high-resolution NMR studies of proteins. In many cases a reliable three-dimensional (3D) structure of the protein is available, for example, from X-ray spectroscopy or homology modeling. Here we introduce the st2nmr program that uses the 3D structure and Nuclear Overhauser Effect spectroscopy (NOESY) peak list(s) to evaluate and optimize trial sequence-specific assignments of spin systems derived from correlation spectra to residues of the protein. A distance-dependent target function that scores trial assignments based on the presence of expected NOESY crosspeaks is optimized in a Monte Carlo fashion. The performance of the program st2nmr is tested on real NMR data of an ,-helical (cytochrome c) and ,-sheet (lipocalin) protein using homology models and/or X-ray structures; it succeeded in completely reproducing the correct sequence-specific assignments in most cases using 2D and/or 15N/13C Nuclear Overhauser Effect (NOE) data. Additionally to amino acid residues the program can also handle ligands that are bound to the protein, such as heme, and can be used as a complementary tool to fully automated assignment procedures. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 335,340, 2002 [source] Structure determination of N -methyl-tetrahydro-5H -indazol-5-onesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2006Kurt A. Josef This paper communicates the (regio) synthesis and a convenient NMR structural assignment method for N -methyl-tetrahydro-5H -indazol-5-one isomers. The cyclization reaction of 7-(hydroxymethylene)-1,4-dioxaspiro[4,5]decan-8-one (3) with methylhydrazine yields, after de-protection predominately the N-2 methyl isomer 2. Analysis of the product ratio and structural assignments are based on NMR data including NOE difference experiments and subsequently confirmed with X-ray crystallography. These findings are in sharp contrast with the literature. The experimental conditions used to optimize the synthesis of the individual isomers are discussed. [source] Dipolar 1,3-cycloaddition of arylnitriloxides on 1,2-dihydroisoquinolines in a two-phase mediumJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 6 2000Said Kitane The 1,3-dipolar cycloaddition of arylnitriloxides on 1,2-dihydroisoquinoline derivatives led to new 3-aryl, 3a-8,9,9a-tetrahydro[5,4- c]-isoxazoloisoquinoline adducts. The regioselectivity of the cycloaddition reactions is discussed on the basis of 1H and 13C NMR data. [source] A comparison of crystallographic and NMR data for thieno[2,3- b:4,5- b,]dipyridine and its monohydroperchlorate saltJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 4 2000Leroy H. Klemm X-ray crystallographic studies of thieno[2,3- b:4,5- b,]dipyridine (1) and its monohydroperchlorate salt (1a) show that 1 is protonated at N1 in ring A and not at N6 in ring C. In each compound individual rings are planar, but there is a small dihedral angle-of-twist between the A and C rings. On going from 1 to 1a the largest changes in bond angles and bond lengths occur in ring A. 1H and l3C nmr spectra of 1 plus the 13C nmr spectrum of 1a are reported. [source] High-resolution H/D exchange studies on the HET-s218,295 prion proteinJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 5 2005Alexis Nazabal Abstract In a search for improved resolution of hydrogen/deuterium (H/D) exchange experiments analyzed by mass spectrometry (HXMS), we evaluated two methodologies for a detailed structural study of solvent accessibility in the case of the HET-s218,295 prion protein. For the first approach, after incubation in the deuterated solvent, aggregated HET-s218,295 was digested with pepsin and the generated peptides were analyzed by nanospray mass spectrometry in an ion trap, with and without collision-induced dissociation (CID). We compared deuterium incorporation in peptides as determined on peptide pseudomolecular ions and on b and y fragments produced by longer peptides under CID conditions. For both b and y fragment ions, an extensive H/D scrambling phenomenon was observed, in contrast with previous studies comparing CID-MS experiments and 1H NMR data. Thus, the spatial resolution of HXMS experiments could not be improved by means of MS/MS data generated by an ion trap mass spectrometer. In a second approach, the incorporation of deuterium was analyzed by MS for 76 peptides of the HET-s218,289 peptide mass fingerprint, and the use of shared boundaries among peptic peptides allowed us to determine deuteration levels of small regions ranging from one to four amino acids. This methodology led to evidence of highly protected regions along the HET-s218,295 sequence. Copyright © 2005 John Wiley & Sons, Ltd. [source] Structural motifs in the maturation process of peptide hormones.JOURNAL OF PEPTIDE SCIENCE, Issue 2 2002The somatostatin precursor. Abstract Synthetic peptides reproducing both the native domain around the dibasic cleavage site of pro-somatostatin, and mutated sequences thereof, previously assayed in site-directed mutagenesis experiments, have been studied by CD in different solvent systems, such as water, TFE/H2O, MeCN/H2O and aqueous SDS, in order to ascertain the ability of each solvent to stabilize secondary structural motifs. A combination of deconvolution methods and empirical calculations, that allow subtraction of the contributions due to unordered structures from the spectra, suggests that mainly two distinct families of ordered conformers containing ,-helix and/or structurally different ,-turns are present in solution, the relative stability of the different conformers depending on the nature of the solvent. The presence of ,-turns is in line with a previous NMR study in DMSO and DMSO/H2O. Comparison of the CD spectra in aqueous SDS of peptides undergoing processing with a sequence not processed in vivo shows that only the latter possesses a stable and detectable ,-helix population. This observation suggests that the structuration involving ,-turns but no ,-helix, which was observed by CD both in SDS and organic solvent/H2O mixtures at high water contents, might be of biological significance. The similarity of this structuration to molecular models obtained from NMR data in DMSO and DMSO/H2O is discussed. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||||||||||||||