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Journal of Computer-Aided Molecular Design

, Volume 21, Issue 8, pp 437–453 | Cite as

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

  • Birgit Schlegel
  • Christian Laggner
  • Rene Meier
  • Thierry Langer
  • David Schnell
  • Roland Seifert
  • Holger Stark
  • Hans-Dieter Höltje
  • Wolfgang Sippl
Article

Abstract

The human histamine H3 receptor (hH3R) is a G-protein coupled receptor (GPCR), which modulates the release of various neurotransmitters in the central and peripheral nervous system and therefore is a potential target in the therapy of numerous diseases. Although ligands addressing this receptor are already known, the discovery of alternative lead structures represents an important goal in drug design. The goal of this work was to study the hH3R and its antagonists by means of molecular modelling tools. For this purpose, a strategy was pursued in which a homology model of the hH3R based on the crystal structure of bovine rhodopsin was generated and refined by molecular dynamics simulations in a dipalmitoylphosphatidylcholine (DPPC)/water membrane mimic before the resulting binding pocket was used for high-throughput docking using the program GOLD. Alternatively, a pharmacophore-based procedure was carried out where the alleged bioactive conformations of three different potent hH3R antagonists were used as templates for the generation of pharmacophore models. A pharmacophore-based screening was then carried out using the program Catalyst. Based upon a database of 418 validated hH3R antagonists both strategies could be validated in respect of their performance. Seven hits obtained during this screening procedure were commercially purchased, and experimentally tested in a [3H]Nα-methylhistamine binding assay. The compounds tested showed affinities at hH3R with K i values ranging from 0.079 to 6.3 μM.

Keywords

Histamine H3 receptor Docking Molecular dynamics GOLD Catalyst Pharmacophore Rhodopsin 

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Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Birgit Schlegel
    • 1
  • Christian Laggner
    • 2
  • Rene Meier
    • 3
  • Thierry Langer
    • 2
  • David Schnell
    • 4
  • Roland Seifert
    • 4
  • Holger Stark
    • 5
  • Hans-Dieter Höltje
    • 1
  • Wolfgang Sippl
    • 3
  1. 1.Institute of Pharmaceutical ChemistryHeinrich-Heine-Universität DüsseldorfDusseldorfGermany
  2. 2.Institute of Pharmaceutical ChemistryLeopold-Franzens-Universität InnsbruckInnsbruckAustria
  3. 3.Department of Pharmaceutical ChemistryMartin-Luther Universität Halle-WittenbergHalle/SaaleGermany
  4. 4.Department of Pharmacology and Toxicology, Institute of PharmacyUniversity of RegensburgRegensburgGermany
  5. 5.Institute of Pharmaceutical Chemistry, Biozentrum, ZAFES/CMPJohann Wolfgang Goethe-UniversitätFrankfurtGermany

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