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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Enade P. Istyastono
  • Saskia Nijmeijer
  • Herman D. Lim
  • Andrea Van De Stolpe
  • Luc Roumen
  • Kooistra, Albert Jelke
  • 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
Issue number23
Pages (from-to)8136-8147
Number of pages12
Publication statusPublished - 8 Dec 2011
Externally publishedYes

ID: 199377037