Mapping histamine H 4 receptor–ligand binding modes

• Published in: MedChemComm 2013, Vol.4 (1), p.193-204
• Main Authors: Schultes, Sabine, Nijmeijer, Saskia, Engelhardt, Harald, Kooistra, Albert J., Vischer, Henry F., de Esch, Iwan J. P., Haaksma, Eric E. J., Leurs, Rob, de Graaf, Chris
• Format: Article
• Language: English
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/C2MD20212C

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 H 4 receptor (H 4 R), 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 H 4 R. By systematically considering different H 4 R 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.