Concept aids drug researchers in screening compounds

By Wai Lang Chu

- Last updated on GMT

Related tags Drug discovery Chemical compound

A new concept to develop a more accurate method for rapidly
screening chemical compounds has been unveiled, which the
researchers say will significantly aid in identifying leads for
drug development and discovery.

The tool is welcome news for scientists who have to trawl through thousands of drug candidates using existing methods that are relatively slow and therefore time consuming. The hope is this new method will give the scientist an added advantage.

Traditional high-throughput screening measures the biological activity of chemical compounds at just one concentration.

In contrast, the new approach, quantitative high-throughput screening (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 characterisation of all the compounds that is far more complete and reliable than traditional methods.

Researchers from the National Institutes of Health (NIH) Chemical Genomics Center used quantitative high-throughput screening to test the activity of varying concentrations of more than 60,000 chemical compounds against pyruvate kinase, an enzyme involved in energy metabolism that is deficient in a form of anaemia 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.

"This new approach produces rich datasets that can be immediately mined for reliable relationships between chemical structure and biological activities,"​ said the study's lead author James Inglese, director of the Biomolecular Screening and Profiling Division at the NIH Chemical Genomics Center.

"This represents a very significant savings of time and resources compared with current iterative screening methods."

To address the limitations of traditional high-throughput screening, the NIH Chemical Genomics Center set about developing a titration-based screening approach that combines a variety of advanced technologies, including microfluidics, low-volume dispensing, high-sensitivity detectors and robotic plate handling.

The NIH researchers used robotic systems to prepare 60,793 chemical compounds at seven or more concentrations across 368 plates, each containing 1,536 microwells.

Over the next 30 hours in an automated format, the plated compounds were exposed to pyruvate kinase, and their biological activities were recorded.

"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 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,"​ he said.

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.

"Upwards of half of the compounds identified as active using the new approach were missed by the traditional screening method,"​ said Doug Auld, co-author of the study and a group leader at the NIH Chemical Genomics Center.

"This tells us that quantitative high-throughput screening is much more sensitive in uncovering chemicals with the potential to be used as biological probes or leads for drug development."

The researchers emphasised that miniaturisation is essential to the efficiency and cost-effectiveness of their new approach.

They noted that their miniaturised, 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.

"We are excited by the power of this approach, developed through the NIH Roadmap for Medical Research, to generate new chemical 'tools' for biological exploration,"​ said NIH Director Elias Zerhouni.

"These tools will help researchers in both the public and private sectors unlock the mysteries of gene function and signalling pathways throughout the human body, opening the door to the development of new drugs."

The study features in the online edition of the Proceedings of the National Academy of Sciences (PNAS).

Related topics Preclinical Research

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