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Molecular Modelling (molecular + modelling)
Terms modified by Molecular Modelling Selected AbstractsAbstracts of QSAR-related Publications: Molecular ModellingMOLECULAR INFORMATICS, Issue 4 2009Article first published online: 3 APR 200 First page of article [source] Abstracts of QSAR-related Publications: Molecular ModellingMOLECULAR INFORMATICS, Issue 3 2009Article first published online: 6 MAR 200 No abstract is available for this article. [source] Abstracts of QSAR-related Publications: Molecular ModellingMOLECULAR INFORMATICS, Issue 2 2009Article first published online: 10 FEB 200 First page of article [source] Abstracts of QSAR-related Publications: Molecular ModellingMOLECULAR INFORMATICS, Issue 9 2008Article first published online: 17 SEP 200 First page of article [source] Abstracts of QSAR-related Publications: Molecular ModellingMOLECULAR INFORMATICS, Issue 10 2006Article first published online: 9 OCT 200 First page of article [source] Abstracts of QSAR-related Publications: Molecular ModellingMOLECULAR INFORMATICS, Issue 7 2006Article first published online: 11 JUL 200 First page of article [source] Abstracts of QSAR-related Publications: Molecular ModellingMOLECULAR INFORMATICS, Issue 4 2006Article first published online: 20 APR 200 First page of article [source] 15th European Symposium on Quantitative Structure-Activity Relationships and Molecular Modelling (Euro-QSAR 2004)MOLECULAR INFORMATICS, Issue 4 2005Esin AKI-SENER No abstract is available for this article. [source] Malondialdehyde modification of myelin oligodendrocyte glycoprotein leads to increased immunogenicity and encephalitogenicityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007Maja Wållberg Abstract Self proteins may become autoantigenic through structural modification. We studied malondialdehydation of recombinant rat (rr) myelin oligodendrocyte glycoprotein (MOG), an autoantigen in multiple sclerosis. Malondialdehyde (MDA) modification changed protein weight and charge, the location of these adducts being mapped by Fourier transform ion cyclotron resonance. Molecular modelling revealed significant differences in the MDA-rrMOG three-dimensional structure. DBA/1 mice immunised with MDA-rrMOG developed greater proliferative responses and more severe experimental autoimmune encephalomyelitis than mice immunised with unmodified rrMOG. MDA-rrMOG was taken up more effectively by antigen-presenting cells (APC), at least partially through scavenger receptors. Exposure to MDA-rrMOG led to increased expression of IL-23, IL-12 and IL-12R, indicating a role not only for increased antigen uptake but also for activation of APC. We thus provide biochemical, structural, immunological and clinical data that suggest that the post-translationally modified form of this myelin autoantigen is a more relevant form of the molecule. [source] Combined Application of Galactose Oxidase and ,- N -Acetylhexosaminidase in the Synthesis of Complex Immunoactive N -Acetyl- D -galactosaminidesADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 7-8 2005Pavla Fialová Abstract A high-yield preparatory procedure for the synthesis of p -nitrophenyl 2-acetamido-2-deoxy-,- D - galacto -hexodialdo-1,5-pyranoside (2) using the galactose oxidase from Dactylium dendroides in a batch reactor was developed. Enzymatic recognition of this aldehyde and the respective uronic acid 3 obtained by NaClO2 oxidation was studied using a set of 36 fungal ,- N -acetylhexosaminidases from Acremonium, Aspergillus, Penicillium and Talaromyces genera. The aldehyde 2 was readily hydrolysed by all tested ,- N -acetylhexosaminidases but neither the uronic acid 3 nor its methyl ester 4 were accepted. Molecular modelling with docking into the active centre of the ,- N -acetylhexosaminidase from Aspergillus oryzae revealed that the aldehyde 2 is processed as a C-6 geminal diol by the enzyme. The aldehyde 2 was tested for transglycosylation reactions using GlcNAc as an acceptor. The ,- N -acetylhexosaminidase from Talaromyces flavus gave the best yields (37%) of the transglycosylation product 2-acetamido-2-deoxy-,- D - galacto -hexodialdo-1,5-pyranosyl-(1,4)-2-acetamido- 2-deoxy- D -glucopyranose, which was oxidised in situ to yield the final product 2-acetamido-2-deoxy-,- D -galactopyranosyluronic acid-(1,4)-2-acetamido-2-deoxy- D -glucopyranose (6). Compounds 3 and 6 were shown to be high-affinity ligands for two natural killer cell activation receptors, NKR-P1A and CD69. For the latter receptor they turned out to be among the best ligands described so far. This increase was obviously due to the presence of a carboxy moiety. [source] Analysis of the surface energy of pharmaceutical powders by inverse gas chromatographyJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2002Ian M. Grimsey Abstract The behavior of pharmaceutical solids, during either processing or use, can be noticeably affected by the surface energetics of the constituent particles. Several techniques exist to measure the surface energy, for example, sessile drop, and dynamic contact angle measurements. Inverse gas chromatography (IGC) is an alternative technique where the powder surface is characterized by the retention behavior of minute quantities of well-characterized vapors that are injected into a column containing the material of interest. Recently published articles using IGC on pharmaceutical powders have ranged from linking surface energetic data with triboelectric charging to studying the effect of surface moisture on surface energetics. Molecular modelling has also recently been used to explore the links between IGC data and the structural and chemical factors that influence surface properties, thereby achieving predictive knowledge regarding powder behavior during processing. In this minireview, the reported applications of IGC in the analysis of pharmaceutical powders are summarized and the major findings highlighted. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:571,583, 2002 [source] Structural studies of 1-(2-hydroxy-4-bromophenyl)-4-methyl-4-imidazolin-2-onesJOURNAL OF PHYSICAL ORGANIC CHEMISTRY, Issue 6 2001Michal K. Cyra Abstract The crystal structure of 1-(2-hydroxy-4-bromophenyl)-3-methyl-4-methyl-4-imidazolin-2-one was determined by x-ray diffraction. The structure is stabilized by intermolecular hydrogen bonds formed between the 2-hydroxy and central groups. Molecular modelling including ab initio calculations at the HF/6,31+G** level revealed that in the gas phase the molecule is stabilized by an intramolecular hydrogen bond. The derivatives with 3-alkyl, benzyl and phenyl substituents were studied by 13C NMR including solid-state 13C CP/MAS NMR [for 1-(2-hydroxy-4-bromophenyl)-3-methyl-4-methyl-4-imidazolin-2-one] and FT-IR methods. The differences in chemical shifts ,,=,,liquid,,,,solid are significant for aromatic carbons C(3) (,2.9,ppm), C(4) (3.6,ppm) and C(5) (,3.9,ppm) and, on the other side of the imidazoline ring, of C(7) (,1.5,ppm). These carbons are adjacent to N(1),C(4), and are subject to the largest changes of the environment during reorientation of the imidazolin-2-one moiety. Copyright © 2001 John Wiley & Sons, Ltd. [source] Calcineurin regulatory subunit is essential for virulence and mediates interactions with FKBP12,FK506 in Cryptococcus neoformansMOLECULAR MICROBIOLOGY, Issue 4 2001Deborah S. Fox Calcineurin is a Ca2+,calmodulin-regulated protein phosphatase that is the target of the immunosuppressive drugs cyclosporin A and FK506. Calcineurin is a heterodimer composed of a catalytic A and a regulatory B subunit. In previous studies, the calcineurin A homologue was identified and shown to be required for growth at 37°C and hence for virulence of the pathogenic fungus Cryptococcus neoformans. Here, we identify the gene encoding the calcineurin B regulatory subunit and demonstrate that calcineurin B is also required for growth at elevated temperature and virulence. We show that the FKR1-1 mutation, which confers dominant FK506 resistance, results from a 6 bp duplication generating a two-amino-acid insertion in the latch region of calcineurin B. This mutation was found to reduce FKBP12,FK506 binding to calcineurin both in vivo and in vitro. Molecular modelling based on the FKBP12,FK506,calcineurin crystal structure illustrates how this mutation perturbs drug interactions with the phosphatase target. In summary, our studies reveal a central role for calcineurin B in virulence and antifungal drug action in the human fungal pathogen C. neoformans. [source] Polymorphism in the nitrate salt of the [Mn(acetylacetonate)2(H2O)2]+ ionACTA CRYSTALLOGRAPHICA SECTION B, Issue 3 2010A. R. Biju The crystallization of [Mn(acac)2(H2O)2]+ from solutions containing excess nitrate leads to the formation of four polymorphs. All polymorphs contain two different types of complex ions, one containing essentially coplanar acac ligands and the other in which the two acac ligands together assume a chair conformation. Molecular modelling using DFT (density-functional theory) calculations shows that the coplanar conformation is the electronically stable one. The hydrogen bonding between the trans -water molecules and the nitrate ion produces a one-dimensional chain of 12-membered rings, which are further organized into a two-dimensional network via a lattice water molecule. Lattice-energy calculations have been carried out to compare the stabilities of the four polymorphs. [source] Molecular modelling of the androgen receptor axis: rational basis for androgen receptor intervention in androgen-independent prostate cancerBJU INTERNATIONAL, Issue 2005ROBERT J. FLETTERICK Androgen depletion in combination with antiandrogenic agents is initially highly effective for treating prostate cancer, and is the recommended treatment for more advanced or higher-grade tumours. However, many tumours eventually become insensitive to androgens, even though the androgen receptor (AR) continues to be expressed. Computational chemistry combined with structural analysis of nuclear receptors and determination of binding affinities of natural and designed coregulators (coactivators and corepressors) provides the theoretical framework for the rational design of novel therapeutic agents directed at the AR. Adding alternative groups to various sites throughout the receptor can alter the conformation of the molecule and its functional binding with coactivators or corepressors. Possible molecules can be identified thoroughly and systematically using intelligent high-throughput screening and FASTrack chemistry (three-dimensional crystallography). Applying these techniques should eventually result in therapeutic agents for androgen-independent prostate cancer that can block binding of AR coactivators while simultaneously increasing binding of AR corepressors. [source] Lasioglossins: Three Novel Antimicrobial Peptides from the Venom of the Eusocial Bee Lasioglossum laticeps (Hymenoptera: Halictidae)CHEMBIOCHEM, Issue 12 2009Václav, ovský Dr. Abstract Three novel structurally related pentadecapeptides, named lasioglossins, were isolated from the venom of the eusocial bee Lasioglossum laticeps. Their primary sequences were established as H-Val-Asn-Trp-Lys-Lys-Val-Leu-Gly-Lys-Ile-Ile-Lys-Val-Ala-Lys-NH2 (LL-I), H-Val-Asn-Trp-Lys-Lys-Ile-Leu-Gly-Lys-Ile-Ile-Lys-Val-Ala-Lys-NH2 (LL-II) and H-Val-Asn-Trp-Lys-Lys-Ile-Leu-Gly-Lys-Ile-Ile-Lys-Val-Val-Lys-NH2 (LL-III). These lasioglossins exhibited potent antimicrobial activity against both Gram-positive and Gram-negative bacteria, low haemolytic and mast cell degranulation activity, and a potency to kill various cancer cells in vitro. The lasioglossin CD spectra were measured in the presence of trifluoroethanol and sodium dodecyl sulfate solution and indicated a high degree of ,-helical conformation. NMR spectroscopy, which was carried out in trifluoroethanol/water confirmed a curved ,-helical conformation with a concave hydrophobic and convex hydrophilic side. To understand the role of this bend on biological activity, we studied lasioglossin analogues in which the Gly in the centre of the molecule was replaced by other amino acid residues (Ala, Lys, Pro). The importance of the N-terminal part of the molecule to the antimicrobial activity was revealed through truncation of five residues from both the N and C termini of the LL-III peptide. C-terminal deamidation of LL-III resulted in a drop in antimicrobial activity, but esterification of the C terminus had no effect. Molecular modelling of LL-III and the observed NOE contacts indicated the possible formation of a bifurcated H-bond between hydrogen from the Lys15 CONH peptide bond and one H of the C-terminal CONH2 to the Ile11 oxygen atom. Such interactions cannot form with C-terminal esterification. [source] Molecular modelling of inclusion compounds from hydrophobic dyes and ,-cyclodextrinCOLORATION TECHNOLOGY, Issue 4 2009Ahmed El-Shafei This paper arises from studies aimed at developing new approaches to combining the fabric formation and coloration steps of fabric processing. A key aspect of these studies involved the evaluation of cyclodextrin (CD)-based compounds as hosts for dye molecules that could be released onto a fabric surface following fabric formation. In this study, experimental data from wide-angle X-ray diffraction and differential scanning calorimetry experiments were used in tandem with molecular modelling studies to confirm the formation of ,-CD,dye complex inclusion compounds and to demonstrate the utility of parameterised model number 3 (PM3) semi-empirical molecular modelling methods for predicting the nature of the preferred ,-CD,dye inclusion compounds. Calculations revealed that the inclusion compounds containing two dye molecules was preferred over the inclusion compound containing one dye molecule. Further, molecular modelling of the inclusion compound obtained using ,-CD linked to an epichlorohydrin-based oligomer and commercial disperse dyes showed inclusion compound formation to be an energetically favourable process. [source] An Efficient Route to 4/5/6 Polycyclic ,-LactamsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 23 2004Nicolas Desroy Abstract The synthesis of 4/5/6 polycyclic ,-lactams by enyne metathesis and Diels,Alder reactions is described. Compared to the synthesis of 4/6/6 and 4/7/6 polycyclic ,-lactams previously reported by our laboratory, formation of the strained 4/5/6 compounds requires alternative reaction conditions. Indeed, the synthesis of the 4/5 bicyclic diene 12 was more difficult than those of the 4/6 (13) and 4/7 (14) dienes. The strain of the 4/5 system could be observed by NMR spectroscopy and molecular modelling. Moreover, the reactivity of 4/5 diene 12 towards Diels,Alder cycloaddition was also different from that of the 4/6 (13) and 4/7 (14) dienes. Cycloadditions with 4/5 diene 12 therefore had to be performed in lithium perchlorate/diethyl ether (LPDE) or in an ionic liquid in order to proceed in good yields with various dienophiles. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Quo vadis neurohypophysial hormone research?EXPERIMENTAL PHYSIOLOGY, Issue 2000Alison J. Douglas Here we highlight just a few of the outstanding questions in the field of neurohypophysial hormones that we envisage will be addressed successfully in the new millennium. To begin, we focus on the regulation of receptors. Despite intensive investigation with new drugs, molecular modelling and transgenic models, the determinants of receptor selectivity remain elusive; there may even be more vasopressin or oxytocin receptor subtypes to be discovered. We discuss the controversy over the interesting studies that indicate modulation of oxytocin receptor-binding by steroids. Oxytocin and vasopressin release and action in the brain are discussed from several aspects. Dendritically released oxytocin acting locally is important for the milk ejection reflex, and similarly released vasopressin is important in regulating patterning of vasopressin neurone activity. Such dendritically released oxytocin and vasopressin is likely to be important in paracrine modulation of neural circuitry involved in neuroendocrine control, and for a range of behaviours. Is it possible that the whole range of behaviours that comprise ,social' (or ,anti-social') or ,maternal' behaviour can be engineered by modifying the expression of just these one or two peptides and their receptors? However, whether gene expression and knockout approaches will answer all the open questions about the real functions of oxytocin and vasopressin remains to be shown. [source] Identification of amino acids in antiplasmin involved in its noncovalent ,lysine-binding-site'-dependent interaction with plasminFEBS JOURNAL, Issue 9 2003Haiyao Wang The lysine-binding-site-mediated interaction between plasmin and antiplasmin is of great importance for the fast rate of this reaction. It also plays an important part in regulating the fibrinolytic enzyme system. To identify structures important for its noncovalent interaction with plasmin, we constructed seven single-site mutants of antiplasmin by modifying charged amino acids in the C-terminal part of the molecule. All the variants were expressed in the Drosophila S2 cell system, purified, and shown to form stable complexes with plasmin. A kinetic evaluation revealed that two mutants of the C-terminal lysine (K452E or K452T) did not differ significantly from wild-type antiplasmin in their reactions with plasmin, in either the presence or absence of 6-aminohexanoic acid, suggesting that this C-terminal lysine is not important for this reaction. On the other hand, modification of Lys436 to Glu decreased the reaction rate about fivefold compared with wild-type. In addition, in the presence of 6-aminohexanoic acid, only a small decrease in the reaction rate was observed, suggesting that Lys436 is important for the lysine-binding-site-mediated interaction between plasmin and antiplasmin. Results from computerized molecular modelling of the C-terminal 40 amino acids support our experimental data. [source] Interpretation of biological activity data of bacterial endotoxins by simple molecular models of mechanism of actionFEBS JOURNAL, Issue 3 2000Vladimir Frecer Lipid A moiety has been identified as the bioactive component of bacterial endotoxins (lipopolysaccharides). However, the molecular mechanism of biological activity of lipid A is still not fully understood. This paper contributes to understanding of the molecular mechanism of action of bacterial endotoxins by comparing molecular modelling results for two possible mechanisms with the underlying experimental data. Mechanisms of action involving specific binding of lipid A to a protein receptor as well as nonspecific intercalation into phospholipid membrane of a host cell were modelled and analysed. As the cellular receptor for endotoxin has not been identified, a model of a peptidic pseudoreceptor was proposed, based on molecular structure, symmetry of the lipid A moiety and the observed character of endotoxin-binding sites in proteins. We have studied the monomeric form of lipid A from Escherichia coli and its seven synthetic analogues with varying numbers of phosphate groups and correlated them with known biological activities determined by the Limulus assay. Gibbs free energies associated with the interaction of lipid A with the pseudoreceptor model and intercalation into phospholipid membrane calculated by molecular mechanics and molecular dynamics methods were used to compare the two possible mechanisms of action. The results suggest that specific binding of lipid A analogues to the peptidic pseudoreceptor carrying an amphipathic cationic binding pattern BHPHB (B, basic; H, hydrophobic; P, polar residue, respectively) is energetically more favourable than intercalation into the phospholipid membrane. In addition, binding affinities of lipid A analogues to the best minimum binding sequence KFSFK of the pseudoreceptor correlated with the experimental Limulus activity parameter. This correlation enabled us to rationalize the observed relationship between the number and position of the phosphate groups in the lipid A moiety and its biological activity in terms of specific ligand,receptor interactions. If lipid A,receptor interaction involves formation of phosphate-ammonium ion-pair(s) with cationic amino-acid residues, the specific mechanism of action was fully consistent with the underlying experimental data. As a consequence, recognition of lipid A variants by an amphipathic binding sequence BHPHB of a host-cell protein receptor might represent the initial and/or rate-determining molecular event of the mechanism of action of lipid A (or endotoxin). The insight into the molecular mechanism of action and the structure of the lipid A-binding pattern have potential implications for rational drug design strategies of endotoxin-neutralizing agents or binding factors. [source] TOP: a new method for protein structure comparisons and similarity searchesJOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 1 2000Guoguang Lu In order to facilitate the three-dimensional structure comparison of proteins, software for making comparisons and searching for similarities to protein structures in databases has been developed. The program identifies the residues that share similar positions of both main-chain and side-chain atoms between two proteins. The unique functions of the software also include database processing via Internet- and Web-based servers for different types of users. The developed method and its friendly user interface copes with many of the problems that frequently occur in protein structure comparisons, such as detecting structurally equivalent residues, misalignment caused by coincident match of C, atoms, circular sequence permutations, tedious repetition of access, maintenance of the most recent database, and inconvenience of user interface. The program is also designed to cooperate with other tools in structural bioinformatics, such as the 3DB Browser software [Prilusky (1998). Protein Data Bank Q. Newslett.84, 3,4] and the SCOP database [Murzin, Brenner, Hubbard & Chothia (1995). J. Mol. Biol.247, 536,540], for convenient molecular modelling and protein structure analysis. A similarity ranking score of `structure diversity' is proposed in order to estimate the evolutionary distance between proteins based on the comparisons of their three-dimensional structures. The function of the program has been utilized as a part of an automated program for multiple protein structure alignment. In this paper, the algorithm of the program and results of systematic tests are presented and discussed. [source] Synthesis of trisubstituted thiophenes designed as progesterone receptor modulatorJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 5 2006Weiqin Jiang When a known 2-[4-morpholino]-3-aryl-5-substituted thiophene, which showed moderate activity as a progesterone antagonist, was superimposed with a potent steroidal progesterone antagonist Org-33628, it showed a fair alignment in most parts of the molecules. According to the molecular modelling, displacement of the morpholine oxygen atom in the thiophene derivative with a carbonyl group would provide a better alignment with the C-3 carbonyl in Org-33628. Thus, a series of novel trisubstituted thiophenes bearing a cyclic ketone moiety was synthesized. Although these compounds only showed weak activities as progesterone receptor antagonists, all target compounds are novel and are fully characterized. [source] Synthesis of linear and cyclic phosphopeptides as ligands for the N -terminal SH2-domain of protein tyrosine phosphatase SHP-1JOURNAL OF PEPTIDE SCIENCE, Issue 7 2005Dr Diana Imhof Abstract Linear and cyclic phosphopeptides related to the pY2267 binding site of the epithelial receptor tyrosine kinase Ros have been synthesized as ligands for the amino-terminal SH2 (src homology) domain of protein tyrosine phosphatase SHP-1. The synthesis was accomplished by Fmoc-based solid-phase methodology using side-chain unprotected phosphotyrosine for the linear and mono-benzyl protected phosphotyrosine for the cyclic peptides. According to molecular modelling, the incorporation of a glycine residue between Lys (position pY,1 relative to phosphotyrosine) and Asp or Glu (position pY+2) was recommended for the cyclic candidates. The preparation of these peptides was successfully performed by the incorporation of a Fmoc-Xxx(Gly-OAll)-OH (Xxx = Asp, Glu) dipeptide building block that was prepared in solution prior to SPPS. The cyclization was achieved with PyBOP following Alloc/OAll-deprotection. This study demonstrates the usefulness of allyl-type protecting groups for the generation of side-chain cyclized phosphopeptides. Alloc/OAll-deprotection and cyclization are compatible with phosphorylated tyrosine. Copyright © 2004 European Peptide Society and John Wiley & Sons, Ltd. [source] The peptaibol antiamoebin as a model ion channel: similarities to bacterial potassium channels,JOURNAL OF PEPTIDE SCIENCE, Issue 11-12 2003Andrias O. O'Reilly Abstract Antiamoebin (AAM) is a polypeptide antibiotic that is capable of forming ion channels in phospholipid membranes; planar bilayer studies have suggested the channels are octamers. The crystal structure of a monomeric form of AAM has provided the basis for molecular modelling of an octameric helical bundle channel. The channel model is funnel-shaped due to a substantial bend in the middle of the polypeptide chain caused by the presence of several imino acids. Inter-monomer hydrogen bonds orientate a ring of glutamine side chains to form a constriction in the pore lumen. The channel lumen is lined both by side chains of Gln11 and by polypeptide backbone carbonyl groups. Electrostatic calculations on the model are compatible with a channel that transports cations across membranes. The AAM channel model is compared with the crystal structures of two bacterial (KcsA and MthK) potassium channels. AAM and the potassium channels exhibit common functional features, such as cation-selectivity and similar single channel conductances. Common structural features include being multimers, each formed from a bundle of eight transmembrane helices, with lengths roughly comparable to the thickness of lipid bilayers. In addition, they all have aromatic amino acids that lie at the bilayer interfaces and which may aid in the stabilization of the transmembrane helices, as well as narrower constrictions that define the ion binding sites or selectivity filters in the pore lumen. The commonality of structural and functional features in these channels thus suggests that antiamoebin is a good, simple model for more complex bacterial and eukaryotic ion channels, capable of providing insight into details of the mechanisms of ion transport and multimeric channel stability. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd. [source] Pharmaceutical and pharmacological importance of peptide transportersJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2008Matthias Brandsch Peptide transport is currently a prominent topic in membrane research. The transport proteins involved are under intense investigation because of their physiological importance in protein absorption and also because peptide transporters are possible vehicles for drug delivery. Moreover, in many tissues peptide carriers transduce peptidic signals across membranes that are relevant in information processing. The focus of this review is on the pharmaceutical relevance of the human peptide transporters PEPT1 and PEPT2. In addition to their physiological substrates, both carriers transport many ,-lactam antibiotics, valaciclovir and other drugs and prodrugs because of their sterical resemblance to di- and tripeptides. The primary structure, tissue distribution and substrate specificity of PEPT1 and PEPT2 have been well characterized. However, there is a dearth of knowledge on the substrate binding sites and the three-dimensional structure of these proteins. Until this pivotal information becomes available by X-ray crystallography, the development of new drug substrates relies on classical transport studies combined with molecular modelling. In more than thirty years of research, data on the interaction of well over 700 di- and tripeptides, amino acid and peptide derivatives, drugs and prodrugs with peptide transporters have been gathered. The aim of this review is to put the reports on peptide transporter-mediated drug uptake into perspective. We also review the current knowledge on pharmacogenomics and clinical relevance of human peptide transporters. Finally, the reader's attention is drawn to other known or proposed human peptide-transporting proteins. [source] Humic acid metal cation interaction studied by spectromicroscopy techniques in combination with quantum chemical calculationsJOURNAL OF SYNCHROTRON RADIATION, Issue 2 2010M. Plaschke Humic acids (HA) have a high binding capacity towards traces of toxic metal cations, thus affecting their transport in aquatic systems. Eu(III),HA aggregates are studied by synchrotron-based scanning transmission X-ray microscopy (STXM) at the carbon K -edge and laser scanning luminescence microscopy (LSLM) at the 5D0,7F1,2 fluorescence emission lines. Both methods provide the necessary spatial resolution in the sub-micrometre range to resolve characteristic aggregate morphologies: optically dense zones embedded in a matrix of less dense material in STXM images correspond to areas with increased Eu(III) luminescence yield in the LSLM micrographs. In the C 1s -NEXAFS of metal-loaded polyacrylic acid (PAA), used as a HA model compound, a distinct complexation effect is identified. This effect is similar to trends observed in the dense fraction of HA/metal cation aggregates. The strongest complexation effect is observed for the Zr(IV),HA/PAA system. This effect is confirmed by quantum chemical calculations performed at the ab initio level for model complexes with different metal centres and complex geometries. Without the high spatial resolution of STXM and LSLM and without the combination of molecular modelling with experimental results, the different zones indicating a `pseudo'-phase separation into strong complexing domains and weaker complexing domains of HA would never have been identified. This type of strategy can be used to study metal interaction with other organic material. [source] Multinuclear magnetic resonance, electrospray ionization time-of-flight mass spectral and molecular modelling characterization of lithocholic acid amide esters with various nitrogen heterocyclesMAGNETIC RESONANCE IN CHEMISTRY, Issue 8 2003Elina Virtanen Abstract 1H, 13C and 15N NMR and electrospray ionization time-of-flight mass spectrometric characterizations of five lithocholate esters of piperazine diamides are described. Two of them are cholaphane-type cyclic structures esterified with 2,2,-bipyridine-4,4 , - and pyridine-2,6-dicarboxylic acid and the other three esters are open structures comprising two or four lithocholyl residues. The conformational preferences of the dimeric congeners were examined by using molecular modelling and variable-temperature 1H NMR techniques. Copyright © 2003 John Wiley & Sons, Ltd. [source] Knockdown resistance to DDT and pyrethroids: from target-site mutations to molecular modellingPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 11 2008TG Emyr Davies Abstract Naturally derived insecticides such as pyrethrum and man-made insecticides such as DDT and the synthetic pyrethroids act on the voltage-gated sodium channel proteins found in insect nerve-cell membranes. The correct functioning of these channels is essential for the normal transmission of nerve impulses, and this process is disrupted by binding of the insecticides, leading to paralysis and eventual death. Some insect pest populations have evolved modifications of the sodium channel protein that inhibit the binding of the insecticide and result in the insect developing resistance. This perspective outlines the current understanding of the molecular processes underlying target-site resistance to these insecticides (termed kdr and super-kdr), and how this knowledge may in future contribute to the design of novel insecticidal compounds. Copyright © 2008 Society of Chemical Industry [source] Identification of isomeric dicaffeoylquinic acids from Eleutherococcus senticosus using HPLC-ESI/TOF/MS and 1H-NMR methodsPHYTOCHEMICAL ANALYSIS, Issue 6 2002Ari Tolonen Abstract Liquid chromatography,electrospray time-of-flight mass spectrometry (HPLC-ESI/TOF/MS) and a novel NMR technique, developed to maximise the sensitivity obtained from the standard NMR spectrometer, have been applied to the identification of the phenolic constituents of Eleutherococcus senticosus. In addition, molecular modelling and dihedral bond angle calculations based on the vicinal 3JHH -coupling constants have been used in the unambiguous assignment of signals in the 1H-NMR spectra. 5,- O -Caffeoylquinic acid and three isomeric compounds, 1,,5,- O -dicaffeoylquinic acid, 3,,5,- O -dicaffeoylquinic acid and 4,,5,- O -dicaffeoylquinic acid, have been isolated and identified from a sample. The isolation and structure determination of the latter two compounds are reported for the first time from this plant. Copyright © 2002 John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||||||||