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New Method for Drug Discovery
"High-throughput screening" isn't a term that comes up too often in polite
conversation outside of scientific circles. But in the scientific community,
it's all the rage. For most of scientific history, researchers discovered new
chemical compounds through a labor-intensive, time-consuming process, manually
testing compounds on tissue samples or laboratory animals. About 15 years ago,
researchers in the pharmaceutical industry developed high-throughput screening
systems, which could quickly test large numbers of compounds on engineered cell
lines and proteins. A new approach developed by NIH's Chemical Genomics Center
takes another step forward, testing several concentrations of each compound.
The results are more accurate and precise, and will speed experiments to probe
biological activities and identify leads for drug discovery.
Current high-throughput screening systems usually focus on a single concentration
of each compound. Testing only one concentration, however, often produces false
positives, which require extensive follow-up testing, and false negatives, which
cause researchers to miss compounds that may have important biological activities.
Dr. Christopher P. Austin, director of the Chemical Genomics Center and senior
author of the new study, said, "To achieve our aim of speeding the discovery
of biological probes and drug targets, we needed a method that offered far greater
precision coupled with the capacity to identify chemicals with a wide spectrum
of biological activities."
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| This ultra-high throughput screening system can evaluate
the biological activity of more than a million chemical compounds per day.
Image by J. Mainquist, courtesy of NIH’s National Human Genome Research
Institute. |
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The researchers developed a screening approach that combines a variety of advanced
technologies, including microfluidics, low-volume dispensing, high-sensitivity
detectors and robotic plate handling. They tested the activity of more than 60,000
chemical compounds against pyruvate kinase, an enzyme involved in energy metabolism
that's deficient in a form of anemia and also implicated in cancer. Using sophisticated
robotic systems, they prepared each compound at seven or more concentrations in
368 "plates," each containing 1,536 microwells. Over the next 30 hours, the compounds
were exposed to the enzyme and their biological activities carefully recorded.
In a paper published online in the Proceedings of the National
Academy of Sciences, the researchers demonstrate that the new approach, called quantitative
high-throughput screening, or qHTS, can characterize the compounds far more
completely and reliably than traditional methods. Dr. Doug Auld, co-author
of the study, said "Upwards of half of the compounds identified as active using
the new approach were missed by the traditional screening method."
The broad adoption of qHTS will both speed and improve the accuracy of screens
for biological probes. It will also accelerate the early phase of the drug discovery
process.
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