Scientists Given Powerful Tool For Drug Discovery By New Research From Magnet La

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Scientists Given Powerful Tool For Drug Discovery By New Research

From Magnet Lab, Scripps Florida

http://www.medicalnewstoday.com/medicalnews.php?newsid=38077

Researchers at Florida State University's National High Magnetic

Field Laboratory and Scripps Florida have developed and evaluated a

robust new system for analyzing how drugs bind to proteins. This

groundbreaking work could speed the delivery of potential new drugs

and improve existing ones.

The work, which appears this week in the journal Analytical

Chemistry, is the first published paper to result from a partnership

between Scripps and a Florida university.

Scripps Florida is a state-of-the-art biomedical research institute

currently located in Jupiter, Fla., on the campus of Florida Atlantic

University. Scripps announced Florida would be home to its second

facility in 2003, with the Florida Legislature agreeing to

appropriate $310 million for the organization's start-up costs.

The National Science Foundation-funded magnet lab is the world leader

in high-magnetic-field research and magnet development. Its

facilities -- with branches at FSU, the University of Florida and Los

Alamos National Laboratory in New Mexico -- are used by faculty and

visiting scientists for research in many disciplines, including

biology and biochemistry.

The collaborative research is focused on getting a more accurate

picture of human proteins, which are the target of most drugs.

Understanding the nature of the interaction between a drug and a

protein -- where the drug attaches and where it doesn't -- is one of

the keys to drug research, because the exact placement of a drug can

determine whether it enhances a natural biological function or

counteracts it.

" By pairing the magnet lab's expertise in high-field research with

Scripps' expertise in protein dynamics and drug development, we can

create a kind of map that shows where drugs bind to the surface of

proteins, " said Alan G. Marshall, director of the lab's Ion Cyclotron

Resonance (ICR) program and the Kasha Professor of Chemistry and

Biochemistry at FSU. " We can do that because our technology is the

best way to generate highly accurate pictures of tiny amounts of

protein molecules. "

The technology referenced by Marshall is a Fourier transform ICR mass

spectrometer built around a 14.5-tesla superconducting magnet. A

tesla is a unit of measurement of a magnetic field's strength. To

illustrate the magnet's relative strength, an MRI machine is 1.5

tesla, and a refrigerator magnet is 0.0025 tesla. Marshall is the co-

inventor of Fourier transform ICR, and his group is widely

acknowledged as the world leader in the development of Fourier

transform ICR techniques and applications.

Marshall said the experiment detailed in Analytical Chemistry can

best be described as " molecular spray painting. " Here's how it works:

The receptor protein with a drug stuck to it is dipped into a solvent

called " heavy water " (deuterium oxide, or D2O). In the portions of

the receptor that can exchange with heavy water (regions not involved

in hydrogen bonding), the natural hydrogen atoms are gradually

replaced by deuterium atoms, which increase the mass from 1 to 2 mass

units. Scientists then dissect the receptor and use the magnet to

weigh pieces of it to see which segments of the receptor remain

covered up by the drug.

The team saw the potential of probing human protein molecules with

this spray-painting technique, but also recognized that the

experiment was limited by several factors. Each test that would have

to be performed would take anywhere from one minute to several hours,

and each measurement would be slow. To ensure the reliability of the

experiment, the process would need to be replicated twice more to

validate the results, adding additional days to the process.

The paper published in Analytical Chemistry lays out the results of

research to improve the technical aspects of the experiment. By

utilizing the high-field ICR magnet and its powerful spectrometer,

coupled with a sample preparation robot, the scientists were able to

extract data that show how the drug alters the dynamics of the

receptor upon binding. This application of the experiment can measure

changes in a fraction of the time -- and show those changes over

time. And the results are highly reproducible.

" This research is important because it gives us a new and very

powerful way to probe the interaction between drugs and proteins, "

said , professor of biochemistry and head of drug

discovery at Scripps Florida. " Because we've now solved many of the

technical problems, this technique is sure to play an even larger

role in understanding the mechanism of action of many classes of

drugs. "

Now that the data acquisition has been automated, the next step is

automating the data analysis. The amount of data generated by the

magnet's high-test mass spectrometer is staggering: 1 million data

points every second. To analyze the data by hand would take a month.

With automated software being developed at the magnet lab, the

analysis will take just a few minutes.