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

Academic Article
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Overview

related to degree

  • Gao, Yu (Tom), Ph.D. in Chemistry, Scripps Research , Transferred from UT Southwestern Medical Center at Dallas 2009 - 2014

authors

  • Doran, T. M.
  • Gao, Yu (Tom)
  • Mendes, K.
  • Dean, S.
  • Simanski, S.
  • Kodadek, Thomas

publication date

  • June 2014

journal

  • ACS Combinatorial Science  Journal

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.

subject areas

  • Antibodies
  • Combinatorial Chemistry Techniques
  • Drug Evaluation, Preclinical
  • Ligands
  • Molecular Structure
  • Particle Size
  • Peptide Library
  • Polystyrenes
  • Protein Binding
  • Surface Properties
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Research

keywords

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

PubMed Central ID

  • PMC4053090

International Standard Serial Number (ISSN)

  • 2156-8952

Digital Object Identifier (DOI)

  • 10.1021/co500030f

PubMed ID

  • 24749624
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Additional Document Info

start page

  • 259

end page

  • 270

volume

  • 16

issue

  • 6

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