Validation of a histamine H3 receptor model through structure–activity relationships for classical H3 antagonists

Lorenzi, Simone; Mor, Marco; Bordi, Fabrizio; Rivara, Silvia; Rivara, Mirko; Morini, Giuseppina; Bertoni, Simona; Ballabeni, Vigilio; Barocelli, Elisabetta; Plazzi, Pier Vincenzo

doi:10.1016/j.bmc.2005.05.072

Cited by 41 publications

(45 citation statements)

References 68 publications

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“…Although in most studies so far published [16,18,27] the imidazole-moiety of antagonists was assumed to interact with E5.46, an inverse placement was assumed in this work for antagonists containing no further basic moieties in their side-chain, resulting in a placement where the imidazole moiety interacted with D3.32. In our opinion, this hypothesis is supported by the binding affinities measured for the antagonists ciproxifan, thioperamide, clobenpropit and NNC-0038-1035 described by Jacobsen et al [23].…”

Section: Discussionmentioning

confidence: 99%

“…The initial sequence-structure alignment was based on multiple sequence alignments, the prediction of secondary structure, transmembrane helices and highly conserved residues identified by Ballesteros et al [21] and resulted to be identical to the alignment shown by Mor and coworkers [27]. After truncating the 3rd intracellular loop to a comparable length as present in the template structure bovine rhodopsin by excising the stretch A240-Q346 from the hH 3 R sequence, amino acid side chain conformations were added using program SCWRL3.0 [30].…”

Section: Methodsmentioning

confidence: 99%

“…Different to the model of Sippl et al which suggested an indirect influence of amino-acids varying between species, in the model of Yao antagonists made a direct contact to those residues, resulting in a ligand placement extending from D3.32 orthogonal to the membrane plane down to residue D2.50 [25,26]. In 2005, a model of the rat H 3 R was published by Lorenzi et al which was used to guide the successful design of further imidazole-containing H 3 R compounds [27]. Antagonists were placed into the homology model starting from the hypothesis that their imidazole ring interacted with E5.…”

Section: Introductionmentioning

confidence: 99%

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

Schlegel

Laggner

Meier

et al. 2007

J Comput Aided Mol Des

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The human histamine H 3 receptor (hH 3 R) 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 hH 3 R and its antagonists by means of molecular modelling tools. For this purpose, a strategy was pursued in which a homology model of the hH 3 R 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 hH 3 R 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 hH 3 R 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 [ 3 H]N a -methylhistamine binding assay. The compounds tested showed affinities at hH 3 R with K i values ranging from 0.079 to 6.3 lM.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Schlegel

Laggner

Meier

et al. 2007

J Comput Aided Mol Des

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“…Homology model of rat H3R was modeled using the bovine rhodopsin template to analyze the binding mode of imidazole derived H3 antagonists [35]. MD simulations were applied to test the stability of the proposed poses.…”

Section: H3 Receptormentioning

confidence: 99%

Structure-based discovery and binding site analysis of histamine receptor ligands

Kingsford-Adaboh

Keserü

2016

Expert Opinion on Drug Discovery

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Introduction: Application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, we review the development of histamine receptors models and their application on drug discovery. Expert opinion: In our opinion, the application of atomistic histamine receptor models played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery, however our analysis also demonstrate that for building H3 and H4 receptor homology models other GPCRs may be more suitable as a template. For these receptors we envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

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“…Histamine H 3 receptor is a G protein-coupled receptor whose activation inhibits the synthesis and release of histamine; in addition to other neurotransmitters from nerve endings and is involved in the modulation of different central nervous system functions. H 3 antagonists have been proposed for their potential usefulness in diseases characterized by impaired neurotransmission and they have demonstrated beneficial effects on learning and food intake in animal models [14,15]. These observations encouraged medicinal chemists to design new H 3 antagonists for treatment of various CNS diseases [8,16,17,18,19,20,6].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2-[{4-(t-amino-1-yl) but-2-yn-1-yl }oxy]-1,3- benzothiazole derivatives as H3-antagonists

Rahmani¹,

kaissi²,

Arafat³

et al. 2014

iosrphr

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Validation of a histamine H3 receptor model through structure–activity relationships for classical H3 antagonists

Cited by 41 publications

References 68 publications

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

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

Structure-based discovery and binding site analysis of histamine receptor ligands

Synthesis of 2-[{4-(t-amino-1-yl) but-2-yn-1-yl }oxy]-1,3- benzothiazole derivatives as H3-antagonists

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