Structure-based discovery and binding site analysis of histamine receptor ligands

ABSTRACT

Introduction: The application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors.

Areas covered: In this paper, the authors review the development of histamine receptor models and their application in drug discovery.

Expert opinion: In the authors’ opinion, the application of atomistic histamine receptor models has played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery; however, our analysis also demonstrates that for building H3 and H4 receptor homology models, other GPCRs may be more suitable as templates. For these receptors, the authors envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

KEYWORDS:

• Histamine
• receptor
• modelling
• structure-based
• virtual screening
• binding mode

Article highlights

• Before 2011 homology models dominated the structure-based drug design of histamine receptor ligands

• Studies on the binding mode analysis of histamine receptor ligands combined with site-directed mutagenesis successfully identified key receptor interaction points

• Virtual screening studies complemented with experimental testing yielded numerous chemical starting points for optimization

• The publication of the H1 receptor in complex with doxepin was a major milestone in the field

• Modelling of the pharmaceutically highly relevant H3 and H4 receptors, that are phylogenetically more distinct from H1R, is still challenging

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the Hungarian Brain Research Program under Grant KTIA NAP 13-2014-0009.