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Firefly luciferase in chemical biology: A compendium of inhibitors, mechanistic evaluation of chemotypes, and suggested use as a reporter
Thorne, Natasha Shen, Min Lea, Wendy A. Simeonov, Anton Lovell, Scott Auld, Douglas S. Inglese, James
Thorne, Natasha
Shen, Min
Lea, Wendy A.
Simeonov, Anton
Lovell, Scott
Auld, Douglas S.
Inglese, James
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Abstract
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, data on compounds acquired from FLuc-dependent assays requires careful analysis as described in this report.
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2012-08-24
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Elsevier
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lovell_firefly.pdf
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Profiling, PubChem, Luciferase, Quantitative high-throughput screening, qHTS, Firefly luciferase, Reporter-gene assays, Adenylate forming enzymes
Citation
Thorne, Natasha, Min Shen, Wendy A. Lea, Anton Simeonov, Scott Lovell, Douglas S. Auld, and James Inglese. "Firefly Luciferase in Chemical Biology: A Compendium of Inhibitors, Mechanistic Evaluation of Chemotypes, and Suggested Use As a Reporter." Chemistry & Biology 19.8 (2012): 1060-072.