In a paper published online in the Proceedings of the National Academy of Sciences (PNAS), a team from the National Institutes for Health (NIH) Chemical Genomics Center demonstrated the feasibility of a new paradigm for profiling every compound in large collections of chemicals.
Traditional high-throughput screening measures the biological activity of chemical compounds at just one concentration. In contrast, the new approach, called quantitative high-throughput screening, or qHTS, tests the biological activity of chemical compounds at seven or more concentration levels spanning four orders of magnitude. The multi-concentration screen produces a pharmacological characterization of all the compounds that is far more complete and reliable than traditional methods.
In their study, the researchers used quantitative high-throughput screening to test the activity of varying concentrations of more than 60,000 chemical compounds against pyruvate kinase, a well-characterized enzyme involved in energy metabolism that is deficient in a form of anemia and also implicated in cancer. The compounds were classified as either activators or inhibitors of the enzyme, with the degree of potency and efficiency associated with the various concentrations of each compound being noted in extensive detail.
Of particular importance, the team was able to take advantage of the new approach to elucidate relationships between the biological activity of a compound and its chemical structure directly from the initial screen – a feat not possible with the traditional method
When the NIH research team compared their quantitative high-throughput screening results with those generated by screening the same chemical compounds with traditional, single-concentration methods, they found the new approach produced a much lower prevalence of false negatives.
“This advance is crucial to NIH’s goal of efficiently profiling the range of biological activities associated with large chemical libraries and making that data swiftly available to the worldwide research community,” said Dr Francis Collins, director of the National Human Genome Research Institute (NHGRI). “Broad adoption of this paradigm should provide robust databases of chemical activity information that will be suitable for accelerating the early phase of the drug discovery process.”