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

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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.

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Notes

  1. low CNS penetration can also be an advantage in situations where a peripheral application of hH3 ligands is pursued, such as the design of nasal decongestants by Schering or cytoprotective agents. [8, 9]

  2. numbering scheme according to Ballesteros et al. [21]: the most conserved residue in each transmembrane segment is assigned position 50. The first number refers to the helical segment.

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Authors and Affiliations

  1. Institute of Pharmaceutical Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40197, Dusseldorf, Germany

    Birgit Schlegel & Hans-Dieter Höltje

  2. Institute of Pharmaceutical Chemistry, Leopold-Franzens-Universität Innsbruck, Innrain 52, Innsbruck, 6020, Austria

    Christian Laggner & Thierry Langer

  3. Department of Pharmaceutical Chemistry, Martin-Luther Universität Halle-Wittenberg, Wolfgang-Langenbeckstr. 4, 06120, Halle/Saale, Germany

    Rene Meier & Wolfgang Sippl

  4. Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040, Regensburg, Germany

    David Schnell & Roland Seifert

  5. Institute of Pharmaceutical Chemistry, Biozentrum, ZAFES/CMP, Johann Wolfgang Goethe-Universität, 60438, Frankfurt, Germany

    Holger Stark

Authors
  1. Birgit Schlegel
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  2. Christian Laggner
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  3. Rene Meier
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  7. Holger Stark
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  8. Hans-Dieter Höltje
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  9. Wolfgang Sippl
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Correspondence to Wolfgang Sippl.

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Schlegel, B., Laggner, C., Meier, R. et al. Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening. J Comput Aided Mol Des 21, 437–453 (2007). https://doi.org/10.1007/s10822-007-9127-x

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  • DOI: https://doi.org/10.1007/s10822-007-9127-x

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