March 25, 2005

Drug discovery gets high-tech screening help

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illustration by Medical Art Group

Drug discovery gets high-tech screening help

Last week the Vanderbilt Institute of Chemical Biology unveiled its new high-throughput screening (HTS) facility, designed to aid drug discovery and studies of basic biology.

The facility, located on the eighth floor of MRBI, includes a “library” of 160,000 small molecules and about $1.5 million worth of computer-controlled, robotically accessible instruments that can test tens of thousands of samples per day for their ability to bind and/or modulate the activity of “target” receptors or enzymes.

An articulate robotic arm moves microplates containing compounds and targets around to various instruments on the “deck” of the screening system. Ultra low-volume liquid handlers squirt nanoliter amounts of the compounds into 384-well plates.

Reactions between compounds and their target molecules are detected using a fluorescence or luminescence method as the plates move through the system. Compounds identified through the initial screen will then be compared to a larger library of 1.2 million molecules maintained by two chemistry companies.

“The idea is you go fishing in our medium-sized pond, you find some actives (also known as 'hits'), and you go to the larger pond and look for cousins of those to establish the structure-activity relationship,” said C. David Weaver, Ph.D., research assistant professor of Pharmacology, who oversees the facility.

“Only in the past five years has high-throughput screening become available to universities. Its value in drug discovery has yet to be determined,” said Weaver, who ran an HTS facility for Bristol-Myers Squibb before joining the Vanderbilt faculty last year.

“You shouldn't honestly expect to find your finished product out of a high throughput screen,” he cautioned.

“You should go in with the expectation that you're going to find something that has some representative activity that you're interested in, and then you're going to have to refine that to understand where the activity comes from.”

Weaver sees the Vanderbilt facility as aiding “tool discovery” as much as drug discovery. When combined with genetic studies, for example, HTS may help scientists better understand and alter pathophysiological pathways such as cancer.

“Unlike in pharma, I don't think there is this super-hard drive (at Vanderbilt) to make this immediately drug-discovery oriented,” Weaver said. “I feel freedom to just ask good scientific questions, and I think this will be a major strength of enabling HTS in university settings.”