Letter abstract
Nature Chemical Biology 1, 146 - 148 (2005)
Published online: 3 July 2005 | doi:10.1038/nchembio718
High-throughput assays for promiscuous inhibitors
Brian Y Feng1,3, Anang Shelat1,3, Thompson N Doman2, R Kip Guy1 & Brian K Shoichet1
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 campaigns1. Several explanations have been proposed to account for promiscuous inhibitors, including chemical reactivity1, 2, interference in assay read-out2, high molecular 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, 6, 7, 8, 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.
- Department of Pharmaceutical Chemistry & Graduate Group in Chemistry and Chemical Biology, 1700 4th St., University of California San Francisco, San Francisco, California 94143-2550, USA.
- Eli Lilly & Company Corporate Center, Drop Code 1523, Indianapolis, Indiana 46285, USA.
- These authors contributed equally to this work.
Correspondence to: R Kip Guy1 e-mail: rguy@cgl.ucsf.edu
Correspondence to: Brian K Shoichet1 e-mail: shoichet@cgl.ucsf.edu
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