High-throughput assays for promiscuous inhibitors

Brian Y. Feng, Anang Shelat, Thompson N. Doman, R. Kip Guy, Brian K. Shoichet

Research output: Contribution to journalArticlepeer-review

308 Scopus citations

Abstract

High-throughput screening (HTS) searches large libraries of chemical compounds for those that can modulate the activity of a particular biological target; it is the dominant technique used in early-stage drug discovery. A key problem in HTS is the prevalence of nonspecific or ‘promiscuous’ inhibitors. These molecules have peculiar properties, act on unrelated targets and can dominate the results from screening campaigns. Several explanations have been proposed to account for promiscuous inhibitors, including chemical reactivity1, 2, interference in assay read-out2, highmolecular flexibility3 and hydrophobicity2, 4. The diversity of these models reflects the apparently unrelated molecules whose behaviors they seek to explain. However, a single mechanism may explain the effects of many promiscuous inhibitors: some organic molecules form large colloid-like aggregates that sequester and thereby inhibit enzymes5. Hits from HTS, leads for drug discovery and even several drugs appear to act through this mechanism at micromolar concentrations5-9. Here, we report two rapid assays for detecting promiscuous aggregates that we tested against 1, 030 ‘drug-like’ molecules. The results from these assays were used to test two preliminary computational models of this phenomenon and as benchmarks to develop new models.

Original languageEnglish
Pages (from-to)146-148
Number of pages3
JournalNature Chemical Biology
Volume1
Issue number3
DOIs
StatePublished - Aug 2005

Bibliographical note

Funding Information:
Supported by GM71630, the QB3 fund and the Burroughs-Wellcome Fund (A.S.). We thank J. Weisman and members of the Shoichet laboratory for reading this manuscript.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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