title: Discovery of nanomolar ligands with novel scaffolds for the histamine H4 receptor by virtual screening.
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.
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France. Electronic address: n.levoin@bioprojet.com.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levoin
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Labeeuw
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Billot
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Calmels
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Danvy
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Krief
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Berrebi-Bertrand
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
authors.forename: Jeanne-Marie
authors.initials: JM
authors.lastname: Lecomte
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Schwartz
authors.affiliation: Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Capet
mesh_terms: D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D011968:Receptors, Histamine / Q000737:chemistry*; D000074040:Receptors, Histamine H4; D054852:Small Molecule Libraries / Q000737:chemistry
chemical_list: C418607:HRH4 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D054852:Small Molecule Libraries
keywords: Docking; Drug discovery; H4 receptor; Histamine; Homology model; Virtual screening