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Chapter 2
Scope of this thesis
The histamine H4 receptor (H4R) is currently seen as a potential drug target for treating
diseases like asthma, allergic rhinitis and pruritis.
1-4
Design of novel, high affinity and
selective H4R ligands is therefore of considerable interest.
1, 5, 6
This new histamine
receptor was reported to be expressed mainly in bone marrow, peripheral blood, spleen,
thymus, small intestine, colon, heart, lung, and also in the CNS.
related publications has steadily increased over time.
1, 6
7-13
The number H4R
In line, the number of known
5, 6
H4R ligands has also increased.
In 2008, at the start of the studies described in this thesis, several series of H4R
1
agonists, antagonists, and inverse agonists, were reported. Interestingly, some of these
ligands are selective for the H4R receptor while other ligands also have considerable
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affinity for other histamine receptors subtypes (i.e., histamine H1, H2 and H3 receptors).
For example, most imidazole-containing H4R ligands also have high affinity for the highly
14,
homologous histamine H3 receptor (H3R).
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As such, the resulting dataset is a
wonderful premise to study the molecular features that are important for ligand-receptor
interactions. The aim of the research described in this thesis is to understand the
molecular determinants of ligands and receptors that are responsible for affinity and
selectivity. Ultimately, this understanding will lead to more efficient drug discovery and hit
optimization. The studies in this thesis involve computational approaches that are
strongly supported by experimental data, including dedicated synthesis of interesting
new ligands and their pharmacological characterization. In addition, molecular biology
approaches enable site-directed mutagenesis studies to make changes on the protein
level. As such, the platform allows three different levels of exploration. 1. Ligand-based
studies can determine the molecular features of compounds that have affinity for the
histamine receptor subtypes. Considering the availability of quality, in-house generated
screening data, quantitative structure-activity studies can be undertaken. Understanding
the features that are important for the ligand to bind to the receptor implies that the
protein receptor site contains complementary features. This information can be used in
subsequent studies. 2. Structure-based studies for GPCRs are complicated as there
are not many crystal structures for GPCR solved (this situation is drastically changing
only in recent months).
It is therefore useful to guide and validate the homology
modeling efforts by using the generated ligand-based information, as well as using
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Chapter 2
experimental data resulting from site-directed mutagenesis and studying ligand-binding
of the resulting mutant receptors. Combined, these studies should lead to detailed
understanding of the interactions that are involved in ligand-H4R receptors. This
understanding can be used in drug discovery approaches. 3. Virtual screening
application can help to determine the accuracy and usefulness of the computational
models. The use of the models in efficient and successful virtual screening campaigns
can be considered as ultimate proof of understanding ligand-receptor interactions.
Gratifyingly, these studies can also lead to the identification of novel hit compounds for
the H4R receptor.
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5.
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9.
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11.
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Chapter 2
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