title: Improving VEGFR-2 docking-based screening by pharmacophore postfiltering and similarity search postprocessing.
abstract: Conventional docking-based virtual screening (VS) of chemical databases is based on the ranking of compounds according to the values retrieved by a scoring function (typically, the binding affinity estimation). However, using the most suitable scoring function for each kind of receptor pocket is not always an effective process to rank compounds, and sometimes neither to distinguish between correct binding modes from incorrect ones. To improve actives from decoys selection, here we propose a three-step VS protocol, which includes the conventional docking step, a pharmacophore postfilter step, and a similarity search postprocess. This VS protocol is retrospectively applied to VEGFR-2 (Kdr-kinase) inhibitors. The resulting docking poses calculated using the Alpha HB scoring function implemented in MOE are postfiltered according to defined pharmacophore interactions (structure based). The selected poses are again ranked according to their molecular similarity (MACCS fingerprint) to the cognate ligand. Results show that both the overall and early VS performance improve the application of this protocol.
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarriá (IQS), Universitat Ramon Llull , Barcelona, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Planesas
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Claramunt
authors.forename: Jordi
authors.initials: J
authors.lastname: Teixidó
authors.forename: José I
authors.initials: JI
authors.lastname: Borrell
authors.forename: Violeta I
authors.initials: VI
authors.lastname: Pérez-Nueno
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D012372:ROC Curve; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D040301:Vascular Endothelial Growth Factor Receptor-2