Discovery of nanomolar ligands with novel scaffolds for the histamine H4 receptor by virtual screening

Eur J Med Chem. 2017 Jan 5;125:565-572. doi: 10.1016/j.ejmech.2016.09.074. Epub 2016 Sep 24.


The involvement of histamine H4 receptor (H4R) in immune cells chemotaxis and mediator release makes it an attractive target for the treatment of inflammation disorders. A decade of medicinal chemistry efforts has led to several promising ligands, although the chemical structures described so far possesses a singular limited diversity. We report here the discovery of novel structures, belonging to completely different scaffolds. The virtual screening was planed as a two-steps process. First, using a "scout screening" methodology, we have experimentally probed the H4R ligand binding site using a small size chemical library with very diverse structures, and identified a hit that further assist us in refining a raw 3D homology model. Second, the refined 3D model was used to conduct a widened virtual screening. This two-steps strategy proved to be very successful, both in terms of structural diversity and hit rate (23%). Moreover, the hits have high affinity for the H4R, with most potent ligands in the nanomolar range.

Keywords: Docking; Drug discovery; H4 receptor; Histamine; Homology model; Virtual screening.

MeSH terms

  • Drug Discovery*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Dynamics Simulation*
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, Histamine / chemistry*
  • Receptors, Histamine H4
  • Small Molecule Libraries / chemistry


  • HRH4 protein, human
  • Ligands
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4
  • Small Molecule Libraries