title: Discovery of novel histamine H4 and serotonin transporter ligands using the topological feature tree descriptor.
abstract: Ligand-based approaches are particularly important in the hit identification process of drug discovery when no structural information on the target is available. Pharmacophore descriptors that use a topological representation of the ligands are usually fast enough to screen large compound libraries effectively when seeking novel lead candidates. One example of this kind is the Feature Tree descriptor, a reduced graph representation implemented in the FTrees software. In this study, we tested the screening efficiency of FTrees by both retrospective and prospective screens using known histamine H4 antagonists and serotonin transporter (SERT) inhibitors as query molecules. Our results demonstrate that FTrees can effectively find actives. Particularly when combined with a subsequent 2D fingerprint-based diversity selection, FTrees was found to be extremely effective at discovering a diverse set of scaffolds. Prospective screening of our in-house compound deck provided several novel H4 and SERT ligands that could serve as suitable starting points for further optimization.
authors.affiliation: Gedeon Richter Plc, Gyömrői út 19-21, H-1103 Budapest, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Kiss
authors.forename: Márk
authors.initials: M
authors.lastname: Sándor
authors.forename: Anikó
authors.initials: A
authors.lastname: Gere
authors.forename: Eva
authors.initials: E
authors.lastname: Schmidt
authors.forename: György T
authors.initials: GT
authors.lastname: Balogh
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.forename: László
authors.initials: L
authors.lastname: Molnár
authors.forename: Christian
authors.initials: C
authors.lastname: Lemmen
authors.forename: György M
authors.initials: GM
authors.lastname: Keseru
mesh_terms: D000465:Algorithms; D017076:Computer-Aided Design; D055808:Drug Discovery; D018494:Histamine Agents / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011968:Receptors, Histamine / Q000737:chemistry*; D000074040:Receptors, Histamine H4; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D012984:Software
chemical_list: D018494:Histamine Agents; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D054852:Small Molecule Libraries; C418607:HRH4 protein, human