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Two-Layer Screen Locates Both Drugs and Targets

Scripps researchers are exploring a new screening method that combines a phenotype-based screen for compounds with a desired cellular effect, and a target-based screen to determine which molecular pathways are being affected. Rather than a purely phenotypic model, which often reveals promising drugs but does not reveal why they work, or a purely target-based model, which may exclude effective compounds because they do not hit a specific molecular target, the Scripps Institute team takes a compromise approach. First, they screen a set of related compounds known to inhibit a broad family of enzymes, looking for compounds with major phenotypic effects. Then, they screen the best candidates against individual enzymes to see which are most strongly inhibited. In a paper published yesterday in Nature Chemical Biology, the researchers use this two-layer screen to discover a drug that relieves diabetes symptoms in mice by inhibiting a hitherto unstudied enzyme.

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