Determination of the binding mode and interacting amino-acids for dibasic H3 receptor antagonists

Bioorg Med Chem. 2013 Aug 1;21(15):4526-9. doi: 10.1016/j.bmc.2013.05.035. Epub 2013 Jun 2.


Due to its involvement in major CNS functions, the histamine H3 receptor (H3R) is the subject of intensive medicinal chemistry investigation, supported by the range of modern drug discovery tools, such as receptor modeling and ligand docking. Although the receptor models described to date share a majority of common traits, they display discrete alternatives in amino-acid conformation, rendering ligand binding modes quite different. Such variations impede structure-based drug design in the H3R field. In the present study, we used a combination of medicinal chemistry, receptor-guided and ligand-based methods to elucidate the binding mode of antagonists. The approaches converged towards a ligand orientation perpendicular to the membrane plane, bridging Glu206 of the transmembrane helix 5 to acidic amino acids of the extracellular loops. This consensus will help future structure-based drug design for H3R ligands.

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / metabolism*
  • Drug Design
  • Drug Discovery
  • Histamine Antagonists / chemistry*
  • Histamine Antagonists / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Protein Binding
  • Receptors, Histamine H3 / chemistry*
  • Receptors, Histamine H3 / metabolism


  • Amino Acids
  • Histamine Antagonists
  • Ligands
  • Receptors, Histamine H3