NIH PROCESS FACILITATES SMALL-MOLECULE DRUG DISCOVERY

A new screening approach can profile compounds in large chemical libraries more accurately and precisely than standard methods, speeding the production of data that can be used to probe biological activities and identify leads for drug discovery, the NIH Chemical Genomics Center has reported. The center is part of a consortium of the Molecular Libraries Screening Centers Network, which has established a collection of 100,000 chemicals from a class of compounds known as small molecules.

In a paper published online, an NIH team demonstrates 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. The new approach, called quantitative high-throughput screening, 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.

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. 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.