Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New paradigm will help identify leads for drug discovery

25.07.2006
NIH roadmap initiative develops more precise method for rapidly screening chemical compounds

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 National Institutes of Health (NIH) Chemical Genomics Center, part of the NIH Roadmap for Medical Research's Molecular Libraries and Imaging Initiative, reported today.

"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. These tools will help researchers in both the public and private sectors unlock the mysteries of gene function and signaling pathways throughout the human body, opening the door to the development of new drugs," said NIH Director Elias A. Zerhouni, M.D.

In a paper published online in the Proceedings of the National Academy of Sciences (PNAS), a team from the NIH Chemical Genomics Center 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. 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.

"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 S. Collins, M.D., Ph.D., 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."

The NIH Chemical Genomics Center, which is based in NHGRI's Division of Intramural Research, is part of an NIH-supported nationwide research consortium of 10 groups, called the Molecular Libraries Screening Centers Network. The network has established a collection of 100,000 chemicals from a class of compounds known as small molecules. Such chemicals can serve as valuable probes in molecular, cellular and whole organism studies of biological functions. Furthermore, most medications used today are small molecules, and this class of chemicals is likely to offer attractive targets for future drug development.

Christopher P. Austin, M.D., the center's director and senior author of the study, explained what motivated his team to develop the new approach. "Traditional high-throughput screening frequently produces false positives and false negatives, and requires extensive follow-up testing. Furthermore, traditional methods often fail to detect compounds that exhibit partial activity or low efficacy, even though such compounds may represent important modulators of biological activity," Dr. Austin 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."

In their study published in PNAS, researchers from the 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, 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. "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 the NIH Chemical Genomics Center.

For most of scientific history, researchers discovered new chemical compounds with medicinal qualities through a labor-intensive, time-consuming process that involved manually testing the compounds on tissue samples or laboratory animals. About 15 years ago, researchers in the pharmaceutical industry developed high-throughput screening systems that tested large numbers of compounds on engineered cell lines and proteins. Still, due to technical demands and limitations, such screening generally has remained focused on a single concentration of each compound.

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. In an experiment designed to test the feasibility, accuracy and efficiency of the new approach, the NIH researchers used sophisticated 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 carefully recorded.

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, Ph.D., 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 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.

Geoff Spencer | EurekAlert!
Further information:
http://www.nih.gov

More articles from Life Sciences:

nachricht The birth of a new protein
20.10.2017 | University of Arizona

nachricht Building New Moss Factories
20.10.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Terahertz spectroscopy goes nano

20.10.2017 | Information Technology

Strange but true: Turning a material upside down can sometimes make it softer

20.10.2017 | Materials Sciences

NRL clarifies valley polarization for electronic and optoelectronic technologies

20.10.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>