A new screening approach can profile compounds in large chemical libraries more accurately and more precisely than standard methods, speeding up the production of data that can be used to probe biological activities and identify leads for drug discovery, researchers at the NIH Chemical Genomics Center (NCGC), part of the NIH Roadmap for Medical Research’s Molecular Libraries and Imaging Initiative, said.

In a paper published online in PNAS, a team from NCGC demonstrated the feasibility of a new paradigm for profiling every compound in large collections of chemicals. 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.

In their study, researchers from NCGC 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 detail.

The researchers emphasized that miniaturization is essential to the efficiency and cost-effectiveness of their new approach. They noted that their miniaturized, seven-point concentration screen consumed less chemicals, used the same amount of enzyme, and required only 1.75-times the number of plates as a traditional single-point concentration screen. Furthermore, the additional plate handling was offset by the elimination of the need to “cherry pick” and re-test compounds in separate experiments, which conserved time and chemical compounds.

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. “This new approach produces rich datasets that can be immediately mined for reliable relationships between chemical structure and biological activities. This represents a very significant savings of time and resources compared with current iterative screening methods,” said the study’s lead author James Inglese, Ph.D., director of the Biomolecular Screening and Profiling Division at NCGC and also editor-in-chief, Assay and Drug Development Technology, a MAL publication.

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