ChemMedChem

Cover image for Vol. 1 Issue 8

August 11, 2006

Volume 1, Issue 8

Pages 749–906

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Reviews
    6. Highlight
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. Cover Picture: Automated Protein–Ligand Crystallography for Structure-Based Drug Design (ChemMedChem 8/2006) (page 749)

      Wijnand T. M. Mooij, Michael J. Hartshorn, Ian J. Tickle, Andrew J. Sharff, Marcel L. Verdonk and Harren Jhoti

      Article first published online: 3 AUG 2006 | DOI: 10.1002/cmdc.200690027

      The cover picture shows a compound bound to thrombin, as determined by automated protein–ligand crystallography. The picture illustrates how a diffraction pattern can be automatically analysed to reveal the binding mode of a compound given a 2D chemical structure and a known 3D structure for the protein. The compound shown was developed by means of fragment-based drug discovery, in which the binding of small, low-affinity molecules is determined by crystallography. This approach to drug discovery is enabled by the automation of protein–ligand crystallography. For details, see the full paper by W. T. M. Mooij et al. on p. 827 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Reviews
    6. Highlight
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
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      Graphical Abstract: ChemMedChem 8/2006 (pages 751–755)

      Article first published online: 3 AUG 2006 | DOI: 10.1002/cmdc.200690028

  3. News

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Reviews
    6. Highlight
    7. Communications
    8. Full Papers
    9. Book Reviews
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    1. From our sister journals: ChemMedChem 8/2006 (pages 756–757)

      Article first published online: 3 AUG 2006 | DOI: 10.1002/cmdc.200690029

  4. Reviews

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Reviews
    6. Highlight
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. The 7 TM G-Protein-Coupled Receptor Target Family (pages 760–782)

      Edgar Jacoby, Rochdi Bouhelal, Marc Gerspacher and Klaus Seuwen

      Article first published online: 31 JUL 2006 | DOI: 10.1002/cmdc.200600134

      Thumbnail image of graphical abstract

      GPCR-directed drug discovery is pursued today with modern approaches including combinatorial library design, structural biology, molecular informatics, and advanced screening technologies for the identification of new compounds that specifically activate or inhibit GPCRs. This Review outlines future progress that may relate today's discoveries to the development of new medicines.

    2. Helicobacter Connections (pages 783–802)

      Barry Marshall

      Article first published online: 3 AUG 2006 | DOI: 10.1002/cmdc.200600153

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      Devotion: In 1984 Barry Marshall performed a risky self experiment. Against a backdrop of skepticism from the mainstream in gastroenterology, the only way he was able to demonstrate that peptic ulcers are caused by bacterial infection was to drink a culture of H. pylori. For this discovery and the ensuing improvements in the treatment of ulcers, Marshall and J. Robin Warren shared the 2005 Nobel Prize for Physiology or Medicine.

  5. Highlight

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Reviews
    6. Highlight
    7. Communications
    8. Full Papers
    9. Book Reviews
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    1. GR Ligands: Can We Improve the Established Drugs? (pages 803–805)

      Hartmut Rehwinkel and Heike Schäcke

      Article first published online: 23 MAY 2006 | DOI: 10.1002/cmdc.200600070

      Thumbnail image of graphical abstract

      Glucocorticoids (GCs) represent the most effective therapy for acute and chronic inflammatory disorders, yet they can elicit severe side effects. New classes of GC receptor ligands appear to have all of the benefits and fewer side effects and have prompted new research into an old drug target. Compound A (shown) is the latest addition to this exciting development.

  6. Communications

    1. Top of page
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    3. Graphical Abstract
    4. News
    5. Reviews
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    7. Communications
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    9. Book Reviews
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    1. Design, Synthesis, and In Vivo Efficacy of Glycine Transporter-1 (GlyT1) Inhibitors Derived from a Series of [4-Phenyl-1-(propylsulfonyl)piperidin-4-yl]methyl Benzamides (pages 807–811)

      Craig W. Lindsley, Zhijian Zhao, William H. Leister, Julie O'Brien, Wei Lemaire, David L. Williams Jr., Tsing-Bau Chen, Raymond S. L. Chang, Maryann Burno, Marlene A. Jacobson, Cyrille Sur, Gene G. Kinney, Douglas J. Pettibone, Philip R. Tiller, Sheri Smith, Nancy N. Tsou, Mark E. Duggan, P. Jeffrey Conn and George D. Hartman

      Article first published online: 29 JUN 2006 | DOI: 10.1002/cmdc.200600097

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      An iterative analogue library synthesis approach rapidly delivered (S)-13 h, a potent, reversible, and selective GlyT1 inhibitor. (S)-13 h selectively increased glycine levels in the prefrontal cortex to 340 % of basal levels and significantly enhanced prepulse inhibition in mice. Thereby, providing strong support for the development of novel antipsychotics based on the NMDA hypofunction hypothesis of schizophrenia.

    2. Synthesis and Activity of Carbazole Derivatives Against Mycobacterium tuberculosis (pages 812–815)

      Taylor A. Choi, Regina Czerwonka, Wolfgang Fröhner, Micha P. Krahl, Kethiri R. Reddy, Scott G. Franzblau and Hans-Joachim Knölker

      Article first published online: 28 JUN 2006 | DOI: 10.1002/cmdc.200600002

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      A series of carbazole derivatives was tested for inhibition of Mycobacterium tuberculosis growth and a mammalian cell line. Among several compounds with anti-TB activity, carbazoles A and B showed MIC values of 4.0 μg mL−1 (8 μM) and 2.2 μg mL−1 (9 μM) respectively, against M. tuberculosis and were relatively nontoxic for the mammalian cell line.

    3. Permeability of Phospholipid Vesicles to the Tumor Antigen Epitope gp100280–288 (pages 816–820)

      Antonella Cavazza, Mario Marini, Giulio C. Spagnoli, Michel Adamina and L. Giorgio Roda

      Article first published online: 3 AUG 2006 | DOI: 10.1002/cmdc.200600019

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      The permeability of phospholipid vesicles to a class I-restricted epitope derived from the melanoma-associated protein, gp100280–288, and its possible effects on epitope degradation by fibroblast-expressed proteolytic enzymes were studied. The results indicate that the majority of the peptide may not be contained within the lipid vesicles when administered for vaccination.

    4. In Situ Polymerized Hydrogels for Repairing Scleral Incisions Used in Pars Plana Vitrectomy Procedures (pages 821–825)

      Michel Wathier, M. Starck Johnson, Michael A. Carnahan, Claxton Baer, Brooks W. McCuen, Terry Kim and Mark W. Grinstaff

      Article first published online: 31 JUL 2006 | DOI: 10.1002/cmdc.200600090

      Thumbnail image of graphical abstract

      New lysine-based dendrimers which upon reaction with a poly(ethylene glycol) di-activated ester afford a soft flexible hydrogel that can be used to seal a wound in the sclerotomy. These wounds are made during the common ophthalmic procedure of a vitrectomy. The rheological and swelling properties of the hydrogel can be tuned by either changing the concentration, the type, and/or the generation of the dendrimers.

  7. Full Papers

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Reviews
    6. Highlight
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. Automated Protein–Ligand Crystallography for Structure-Based Drug Design (pages 827–838)

      Wijnand T. M. Mooij, Michael J. Hartshorn, Ian J. Tickle, Andrew J. Sharff, Marcel L. Verdonk and Harren Jhoti

      Article first published online: 10 JUL 2006 | DOI: 10.1002/cmdc.200600074

      Thumbnail image of graphical abstract

      An approach to automate protein–ligand crystallography is presented, featuring a novel ligand placement procedure that seeks solutions with sensible protein–ligand interactions and ligand geometries. The methods described significantly increase the number of structures available to structure-based drug design, and enable fragment-based drug design by crystallography.

    2. Integrated Approach Using Protein and Ligand Information to Analyze Selectivity- and Affinity-Determining Features of Carbonic Anhydrase Isozymes (pages 839–853)

      Alexander Hillebrecht, Claudiu T. Supuran and Gerhard Klebe

      Article first published online: 10 JUL 2006 | DOI: 10.1002/cmdc.200600083

      Thumbnail image of graphical abstract

      Elucidation of selectivity-determining features: several 3D QSAR methods were applied to a set of about 140 ligands to identify features which determine selectivity towards carbonic anhydrases I, II, and IV. This study describes how protein and ligand information may be exploited simultaneously and provides a synopsis of the approaches used therein.

    3. FlexNovo: Structure-Based Searching in Large Fragment Spaces (pages 854–868)

      Jörg Degen and Matthias Rarey

      Article first published online: 31 JUL 2006 | DOI: 10.1002/cmdc.200500102

      Thumbnail image of graphical abstract

      Filtering through: A novel molecular design software package, FlexNovo, based on the concept of chemical fragment spaces, has been applied to inhibitor design for four targets of pharmaceutical interest. FlexNovo is shown to reproduce known structural motifs and binding modes. The results underline the importance of using target-specific (tailored) filter functions as well as pharmacophore-type constraints for guiding the search process.

    4. Phosphopeptide Ligands of the SHP-1 N-SH2 Domain: Effects on Binding and Stimulation of Phosphatase Activity (pages 869–877)

      Kornelia Hampel, Ina Kaufhold, Martin Zacharias, Frank D. Böhmer and Diana Imhof

      Article first published online: 31 JUL 2006 | DOI: 10.1002/cmdc.200600037

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      High-affinity peptides that target the N-terminal SH2 domain of SHP-1 were investigated for their ability to stimulate the phosphatase activity of both wild-type and mutant enzyme forms. This study is based on initial investigations of the structural requirements for the SHP-1 N-SH2 ligand binding of peptides derived from the natural interaction partner Ros EGLN-pY2267-MVL (image: PDB code 1aya).

    5. The Predicted 3D Structures of the Human M1 Muscarinic Acetylcholine Receptor with Agonist or Antagonist Bound (pages 878–890)

      Joyce Yao-chun Peng, Nagarajan Vaidehi, Spencer E. Hall and William A. Goddard III

      Article first published online: 31 JUL 2006 | DOI: 10.1002/cmdc.200600047

      Thumbnail image of graphical abstract

      The power of prediction: The 3D structure of the human M1 muscarinic receptor and the binding sites of seven agonists and antagonists were predicted using the MembStruk and HierDock methods. The results correlate well with mutagenesis data and measured binding affinities. The predicted binding site provides structural insight that will aid structure-based drug design for better ligands.

    6. Improving Potency, Selectivity, and Water Solubility of Adenosine A1 Receptor Antagonists: Xanthines Modified at Position 3 and Related Pyrimido[1,2,3-cd]purinediones (pages 891–902)

      Stefanie Weyler, Friederike Fülle, Martina Diekmann, Britta Schumacher, Sonja Hinz, Karl-Norbert Klotz and Christa E. Müller

      Article first published online: 10 JUL 2006 | DOI: 10.1002/cmdc.200600066

      Thumbnail image of graphical abstract

      The structure–activity relationships of 3-substituted xanthine derivatives were investigated. 1-Butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine exhibited sub-nanomolar Ki values for rat and human adenosine A1 receptors and was highly A1-selective. 8-Alkyl-2-(3-noradamantyl)pyrimido[1,2,3-cd]purine-8,10-diones represent a new class of potent, selective adenosine A1 receptor antagonists.

  8. Book Reviews

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Reviews
    6. Highlight
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
  9. Preview

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Reviews
    6. Highlight
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. Preview: ChemMedChem 8/2006 (page 906)

      Article first published online: 3 AUG 2006 | DOI: 10.1002/cmdc.200690030

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