Molecular determinants of ligand binding modes in the histamine H 4 receptor: Linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies

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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 Graaf

The histamine H 4 receptor (H 4R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H 3 receptor (H 3R), two acidic residues in the H 4R binding pocket, D 3.32 and E 5.46, act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H 4R ligands. Given the symmetric distribution of these complementary pharmacophore features in H 4R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H 4R-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 H 4R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H 4R 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 H 4R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H 4R and can be used as a general approach to elucidate the structure of protein-ligand complexes.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume54
Issue number23
Pages (from-to)8136-8147
Number of pages12
ISSN0022-2623
DOIs
Publication statusPublished - 8 Dec 2011
Externally publishedYes

ID: 199377037