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A high-throughput screen for aggregation-based inhibition in a large compound library.

Brian Y Feng1, Anton Simeonov, Ajit Jadhav

  • 1Department of Pharmaceutical Chemistry & Graduate Group in Chemistry and Chemical Biology, 1700 4th Street, University of California San Francisco, San Francisco, California 94158-2330, USA.

Journal of Medicinal Chemistry
|April 24, 2007
PubMed
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High-throughput screening (HTS) can yield false positives due to molecule aggregation. This study demonstrates large-scale identification of these aggregate-based inhibitors, finding they comprise 95% of actives in a chemical library.

Area of Science:

  • Drug discovery and chemical biology
  • Biophysical chemistry
  • High-throughput screening methodologies

Background:

  • High-throughput screening (HTS) is crucial for identifying drug leads but is prone to false positives.
  • Colloidal aggregation of organic molecules can cause non-specific enzyme inhibition, leading to false-positive hits in HTS.
  • Understanding and mitigating aggregation-based inhibition is vital for accurate drug discovery.

Purpose of the Study:

  • To assess the feasibility of large-scale identification of aggregate-based inhibition using detergent sensitivity.
  • To quantify the prevalence of aggregate-based inhibition among hits from a large chemical library screen.
  • To investigate the correlation between aggregate-based inhibition and dose-response curve steepness.

Main Methods:

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  • Screened 70,563 molecules from the NCGC library for detergent-sensitive inhibition across multiple concentrations.
  • Obtained dose-response curves for all screened molecules to analyze inhibition patterns.
  • Confirmed findings by retesting 31 selected library molecules in secondary low-throughput experiments.

Main Results:

  • Detergent-dependent identification of aggregate-based inhibition is feasible on a large scale.
  • 1204 out of 1274 identified inhibitors (95%) were confirmed as aggregate-based.
  • Aggregate-based inhibition showed a correlation with steep dose-response curves, though not absolute.

Conclusions:

  • Large-scale, detergent-based screening effectively identifies aggregate-based inhibitors, a common source of false positives.
  • The vast majority of identified actives in this screen were due to aggregation, highlighting a significant challenge in HTS.
  • Dose-response curve steepness can serve as an indicator of potential aggregation-based inhibition.