4.3 Article

Virtual screening to enrich hit lists from high-throughput screening: A case study on small-molecule inhibitors of angiogenin

Journal

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 50, Issue 1, Pages 81-93

Publisher

WILEY
DOI: 10.1002/prot.10270

Keywords

virtual screening; ligand docking; high-throughput screening; angiogenin; consensus scoring; false positives; enrichment; enzyme inhibitor; ribonuclease

Funding

  1. NCI NIH HHS [CA78048, CA88738] Funding Source: Medline
  2. NIGMS NIH HHS [GM62566] Funding Source: Medline
  3. NATIONAL CANCER INSTITUTE [P01CA078048, R01CA088738] Funding Source: NIH RePORTER
  4. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P01GM062566] Funding Source: NIH RePORTER

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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 (similar to18,000 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.

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