Virtual screening of biogenic amine-binding G-protein coupled receptors: comparative evaluation of protein- and ligand-based virtual screening protocols.

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.