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

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

Author information

1
Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France. Electronic address: n.levoin@bioprojet.com.
2
Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.

Abstract

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

PMID:
27718472
DOI:
10.1016/j.ejmech.2016.09.074
[Indexed for MEDLINE]

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