title: Virtual screening of biogenic amine-binding G-protein coupled receptors: comparative evaluation of protein- and ligand-based virtual screening protocols.
abstract: In this paper, we compare protein- and ligand-based virtual screening techniques for identifying the ligands of four biogenic amine-binding G-protein coupled receptors (GPCRs). For the screening of the virtual compound libraries, we used (1) molecular docking into GPCR homology models, (2) ligand-based pharmacophore and Feature Tree models, (3) three-dimensional (3D)-similarity searches, and (4) statistical methods [partial least squares (PLS) and partial least squares discriminant analysis (PLS-DA) models] based on two-dimensional (2D) molecular descriptors. The comparison of the different methods in retrieving known antagonists from virtual libraries shows that in our study the ligand-based pharmacophore-, Feature Tree-, and 2D quantitative structure-activity relationship (QSAR)-based screening techniques provide enrichment factors that are higher than those provided by molecular docking into the GPCR homology models. Nevertheless, the hit rates achieved when docking with GOLD and ranking the ligands with GoldScore (up to 60% among the top-ranked 1% of the screened databases) are still satisfying. These results suggest that docking into GPCR homology models can be a useful approach for lead finding by virtual screening when either little or no information about the active ligands is available.
authors.affiliation: Aventis Pharma Deutschland GmbH, Ein Unternehmen der Sanofi-Aventis Gruppe, Chemical Sciences, Drug Design, 65926 Frankfurt am Main, Germany. Andreas.Evers@sanofi-aventis.com
authors.forename: Andreas
authors.initials: A
authors.lastname: Evers
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hessler
authors.forename: Hans
authors.initials: H
authors.lastname: Matter
authors.forename: Thomas
authors.initials: T
authors.lastname: Klabunde
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D001665:Binding Sites; D001679:Biogenic Amines / Q000737:chemistry*; D016208:Databases, Factual; D065127:Dopamine D2 Receptor Antagonists; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000737:chemistry; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry; D017448:Receptors, Dopamine D2 / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D058830:Serotonin 5-HT2 Receptor Antagonists
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D001679:Biogenic Amines; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D043643:Receptor, Muscarinic M1; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D058830:Serotonin 5-HT2 Receptor Antagonists