Discovery of novel histamine H4 and serotonin transporter ligands using the topological feature tree descriptor

J Chem Inf Model. 2012 Jan 23;52(1):233-42. doi: 10.1021/ci2004972. Epub 2011 Dec 28.

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.

MeSH terms

  • Algorithms
  • Computer-Aided Design
  • Drug Discovery
  • Histamine Agents / chemistry*
  • Histamine Agents / pharmacology
  • Humans
  • Molecular Structure
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, Histamine / chemistry*
  • Receptors, Histamine H4
  • Selective Serotonin Reuptake Inhibitors / chemistry*
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / chemistry*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Software*

Substances

  • HRH4 protein, human
  • Histamine Agents
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Small Molecule Libraries