Mapping histamine H4 receptor-ligand binding modes

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

doi:10.1039/c2md20212c

Mapping histamine H₄ receptor-ligand binding modes

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^*

^*Corresponding author for this work

30 Citations (Scopus)

Abstract

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 language	English
Journal	MedChemComm
Volume	4
Issue number	1
Pages (from-to)	193-204
Number of pages	12
ISSN	2040-2503
DOIs	https://doi.org/10.1039/c2md20212c
Publication status	Published - 1 Jan 2013
Externally published	Yes

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title = "Mapping histamine H4 receptor-ligand binding modes",

abstract = "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.",

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T1 - Mapping histamine H4 receptor-ligand binding modes

AU - Schultes, Sabine

AU - Nijmeijer, Saskia

AU - Engelhardt, Harald

AU - Kooistra, Albert J.

AU - Vischer, Henry F.

AU - De Esch, Iwan J P

AU - Haaksma, Eric E J

AU - Leurs, Rob

AU - De Graaf, Chris

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

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Mapping histamine H₄ receptor-ligand binding modes

Abstract

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