Utility of redundant combinatorial libraries in distinguishing high and low quality screening hits

Todd M. Doran, Yu Gao, Kimberly Mendes, Sonja Dean, Scott Simanski, Thomas Kodadek

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Large one-bead one-compound (OBOC) combinatorial libraries can be constructed relatively easily by solid-phase split and pool synthesis. The use of resins with hydrophilic surfaces, such as TentaGel, allows the beads to be used directly in screens for compounds that bind selectively to labeled proteins, nucleic acids, or other biomolecules. However, we have found that this method, while useful, has a high false positive rate. In other words, beads that are scored as hits often display compounds that prove to be poor ligands for the target of interest when they are resynthesized and carried through validation trials. This results in a significant waste of time and resources in cases where putative hits cannot be validated without resynthesis. Here, we report that this problem can be largely eliminated through the use of redundant OBOC libraries, where more than one bead displaying the same compound is present in the screen. We show that compounds isolated more than once are likely to be high quality ligands for the target of interest, whereas compounds isolated only once have a much higher likelihood of being poor ligands. While the use of redundant libraries does limit the number of unique compounds that can be screened at one time in this format, the overall savings in time, effort, and materials makes this a more efficient route to the isolation of useful ligands for biomolecules.

Original languageEnglish (US)
Pages (from-to)259-270
Number of pages12
JournalACS Combinatorial Science
Volume16
Issue number6
DOIs
StatePublished - Jun 9 2014

Keywords

  • OBOC library
  • antibody screen
  • antigen surrogate
  • nonspecific binding
  • peptoids
  • redundant library
  • serum screen

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