The development of a high-throughput screen to identify false positives from chemical screens has been reported in a paper in the August issue of Nature Chemical Biology. High-throughput chemical screening is a major way that pharmaceutical and biotechnology companies identify inhibitors as new drug leads. A rapid method for eliminating nonspecific inhibitors from true "hits" promises to speed up the drug discovery process.

In looking at more than a thousand chemicals, Kip Guy and Brian Shoichet and colleagues found that even for small molecules considered to be "drug-like," a significant number caused inhibition of an enzyme assay due to general aggregation rather than specific inhibition. To identify these nonspecific inhibitors, they developed two rapid screens, one based on detergent sensitivity and the other based on light scattering. These results were then used to develop computational models for predicting small molecules likely to aggregate.

Although these results suggest that aggregation is a common problem in chemical screening, they also provide an approach for quickly eliminating these red herrings.

DOI: 10.1038/nchembio718

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