Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 5, Pages 1450-1458Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm8014525
Keywords
-
Categories
Funding
- NIH Roadmap for Medical Research
- National Human Genome Research Institute
Ask authors/readers for more resources
We measured the druggability of the ATP-dependent luciferase derived from the firefly Photuris pennsylvanica that was optimized using directed evolution (Ultra-Glo, Promega). Quantitative high-throughput screening (qHTS) was used to determine IC(50)S of 198899 samples against a formulation of Ultra-Glo luciferase (Kinase-Glo). We found that only 0.1 % of the Kinase-Glo inhibitors showed an IC(50) < 10 mu M compared to 0.9% found from a previous qHTS against the firefly luciferase from Photinus pyralis (lucPpy). Further, the maximum affinity identified in the lucPpy qHTS was 50 nM, while for Kinase-Glo this value increased to 600 nM. Compounds with interactions stretching outside the luciferin binding pocket were largely lost with Ultra-Glo luciferase. Therefore, Ultra-Glo luciferase will show less compound interference when used as an ATP sensor compared to lucPpy. This study demonstrates the power of large-scale quantitative analysis of structure-activity relationships (> 100K compounds) in addressing important questions such as a target's druggability.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available