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July 28, 2006
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."
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.