Journal
CHEMISTRY & BIOLOGY
Volume 19, Issue 8, Pages 1060-1072Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2012.07.015
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Funding
- Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [1 U54 MH084681-01]
- National Human Genome Research Institute, National Institutes of Health
- Hauptman-Woodward Medical Research Institute
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- National Center for Research Resources [5P20RR017708-10]
- National Institute of General Medical Sciences from the National Institutes of Health [8 P20 GM103420-10]
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Firefly luciferase (FLuc) is frequently used as a reporter in high-throughput screening assays, owing to the exceptional sensitivity, dynamic range, and rapid measurement that bioluminescence affords. However, interaction of small molecules with FLuc has, to some extent, confounded its use in chemical biology and drug discovery. To identify and characterize chemotypes interacting with FLuc, we determined potency values for 360,864 compounds found in the NIH Molecular Libraries Small Molecule Repository, available in PubChem. FLuc inhibitory activity was observed for 12% of this library with discernible SAR. Characterization of 151 inhibitors demonstrated a variety of inhibition modes, including FLuc-catalyzed formation of multisubstrate adduct enzyme inhibitor complexes. As in some cell-based FLuc reporter assays, compounds acting as FLuc inhibitors yield paradoxical luminescence increases, thus data on compounds acquired from FLuc-dependent assays require careful analysis as described here.
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