title: Here be dragons: docking and screening in an uncharted region of chemical space.
abstract: To compare virtual and high-throughput screening in an unbiased way, 50,000 compounds were docked into the 3-dimensional structure of dihydrofolate reductase prospectively, and the results were compared to a subsequent experimental screening of the same library. Undertaking these calculations demanded careful database curation and control calculations with annotated inhibitors. These ultimately led to a ranked list of more likely and less likely inhibitors and to the prediction that relatively few inhibitors would be found in the empirical screen. The latter prediction turned out to be correct, with arguably no validated inhibitors found experimentally. Subsequent retesting of high-scoring docked molecules may have found 2 true inhibitors, although this remains uncertain due to experimental ambiguities. The implications of this study for screening campaigns are considered.
authors.affiliation: University of California, San Francisco, Department of Pharmaceutical Chemistry, 1700 4th Street, San Francisco, CA 94143-2550, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: John J
authors.initials: JJ
authors.lastname: Irwin
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
mesh_terms: D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D019992:Databases as Topic; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008024:Ligands; D008954:Models, Biological; D008956:Models, Chemical; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D008024:Ligands; D013762:Tetrahydrofolate Dehydrogenase