title: Evaluation of library ranking efficacy in virtual screening.
abstract: We present the results of a comprehensive study in which we explored how the docking procedure affects the performance of a virtual screening approach. We used four docking engines and applied 10 scoring functions to the top-ranked docking solutions of seeded databases against six target proteins. The scores of the experimental poses were placed within the total set to assess whether the scoring function required an accurate pose to provide the appropriate rank for the seeded compounds. This method allows a direct comparison of library ranking efficacy. Our results indicate that the LigandFit/Ligscore1 and LigandFit/GOLD docking/scoring combinations, and to a lesser degree FlexX/FlexX, Glide/Ligscore1, DOCK/PMF (Tripos implementation), LigandFit1/Ligscore2 and LigandFit/PMF (Tripos implementation) were able to retrieve the highest number of actives at a 10% fraction of the database when all targets were looked upon collectively. We also show that the scoring functions rank the observed binding modes higher than the inaccurate poses provided that the experimental poses are available. This finding stresses the discriminatory ability of the scoring algorithms, when better poses are available, and suggests that the number of false positives can be lowered with conformers closer to bioactive ones.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Computer Assisted Drug Discovery, Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477, USA. mkontoyi@yahoo.com
authors.forename: Maria
authors.initials: M
authors.lastname: Kontoyianni
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Sokol
authors.forename: Laura M
authors.initials: LM
authors.lastname: McClellan
mesh_terms: D000465:Algorithms; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000187:drug effects; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects; D008024:Ligands; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000187:drug effects; D013820:Thermolysin / Q000037:antagonists & inhibitors / Q000737:chemistry; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D011506:Proteins; D013762:Tetrahydrofolate Dehydrogenase; D013937:Thymidine Kinase; D016333:HIV Protease; D019278:Matrix Metalloproteinase 3; D013820:Thermolysin; D002256:Carbonic Anhydrases