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Molecular Determinants of Ligand Binding Modes in the Histamine H4 Receptor: Linking Ligand-Based Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) Models to in Silico Guided Receptor Mutagenesis Studies
journal contribution
posted on 2011-12-08, 00:00 authored by Enade
P. Istyastono, Saskia Nijmeijer, Herman D. Lim, Andrea van de Stolpe, Luc Roumen, Albert J. Kooistra, Henry F. Vischer, Iwan J. P. de Esch, Rob Leurs, Chris de GraafThe histamine H4 receptor (H4R)
is a G protein-coupled
receptor (GPCR) that plays an important role in inflammation. Similar
to the homologous histamine H3 receptor (H3R),
two acidic residues in the H4R binding pocket, D3.32 and E5.46, act as essential hydrogen bond acceptors of
positively ionizable hydrogen bond donors in H4R ligands.
Given the symmetric distribution of these complementary pharmacophore
features in H4R and its ligands, different alternative
ligand binding mode hypotheses have been proposed. The current study
focuses on the elucidation of the molecular determinants of H4R–ligand binding modes by combining (3D) quantitative
structure–activity relationship (QSAR), protein homology modeling,
molecular dynamics simulations, and site-directed mutagenesis studies.
We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea)
derivatives to investigate H4R–ligand interactions
and ligand binding orientations. Interestingly, our studies indicate
that clobenpropit (2) itself can bind to H4R in two distinct binding modes, while the addition of a cyclohexyl
group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H4R binding pocket. Our ligand-steered, experimentally supported protein
modeling method gives new insights into ligand recognition by H4R and can be used as a general approach to elucidate the structure
of protein–ligand complexes.
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Keywords
histamine H 3 receptorclobenpropit isothiourea moietyligand binding orientations3RH 4R binding pocketprotein modeling methodH 4R interactionsVUFLigand Binding ModesSilico Guided Receptor Mutagenesis StudiesThe histamine H 4 receptorionizable hydrogen bond donorsHistamine H 4 Receptorhydrogen bond acceptorsH 4R ligandsGPCRQSARH 4Ralternative ligand binding mode hypothesesH 4R binding modes
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