Mapping histamine H4 receptor-ligand binding modes

Research output: Contribution to journalJournal article

Sabine Schultes, Saskia Nijmeijer, Harald Engelhardt, Albert J. Kooistra, Henry F. Vischer, Iwan J P De Esch, Eric E J Haaksma, Rob Leurs, Chris De Graaf

The increasing number of G protein-coupled receptor (GPCR) crystal structures offers new opportunities for histamine receptor homology modeling. However, computational prediction of ligand binding modes in GPCRs such as the histamine H4 receptor (H4R), a receptor that plays an important role in inflammation, remains a challenging task. In the current work we have combined complementary in silico receptor modeling approaches with in vitro ligand structure-activity relationship (SAR) and protein site-directed mutagenesis studies to elucidate the binding modes of different ligand classes in H4R. By systematically considering different H4R modelling templates, ligand binding poses, and ligand protonation states in combination with docking and MD simulations we are able to explain ligand-specific mutation effects and subtle differences in ligand SAR. Our studies confirm that a combined theoretical and experimental approach represents a powerful strategy to map ligand-protein interactions.

Original languageEnglish
JournalMedChemComm
Volume4
Issue number1
Pages (from-to)193-204
Number of pages12
ISSN2040-2503
DOIs
Publication statusPublished - 1 Jan 2013
Externally publishedYes

ID: 199376791