Virtual screening to enrich hit lists from high-throughput screening: a case study on small-molecule inhibitors of angiogenin.
"Hit lists" generated by high-throughput screening (HTS) typically contain a large percentage of false positives, making follow-up assays necessary to distinguish active from inactive substances. Here we present a method for improving the accuracy of HTS hit lists by computationally based virtual screening (VS) of the corresponding chemical libraries and selecting hits by HTS/VS consensus. This approach was applied in a case study on the target-enzyme angiogenin, a potent inducer of angiogenesis. In conjunction with HTS of the National Cancer Institute Diversity Set and ChemBridge DIVERSet E (approximately 18,000 compounds total), VS was performed with two flexible library docking/scoring methods, DockVision/Ludi and GOLD. Analysis of the results reveals that dramatic enrichment of the HTS hit rate can be achieved by selecting compounds in consensus with one or both of the VS functions. For example, HTS hits ranked in the top 2% by GOLD included 42% of the true hits, but only 8% of the false positives; this represents a sixfold enrichment over the HTS hit rate. Notably, the HTS/VS method was effective in selecting out inhibitors with midmicromolar dissociation constants typical of leads commonly obtained in primary screens.
Jenkins
Jeremy L
JL
Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Cambridge, Massachusetts 02139, USA.
Kao
Richard Y T
RY
Shapiro
Robert
R
D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D015203:Reproducibility of Results; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D004791:Enzyme Inhibitors; D008024:Ligands; C046366:angiogenin; D012259:Ribonuclease, Pancreatic