The Buffalo News

RESEARCHERS REPORT MOLECULAR BREAKTHROUGH WORK BY BUFFALO TEAM AIMS TO SPEED DEVELOPMENT OF TARGETED DRUGS

Published on April 25, 1992
Author:    By MIKE VOGEL - News Staff Reporter
© The Buffalo News Inc.

A Buffalo-based research team led by a Nobel laureate today was to unveil a new "shake-and-bake" research method that could speed the development of drugs targeting a wide range of diseases.

The technique, which uses a combination of parallel

supercomputers and human insight, cuts the time involved in "solving" the molecular structures of complex chemical compounds from years to just a few weeks -- or, in some cases, hours. By determining the structure of complex proteins and other molecules, researchers hope that it will be possible to understand how living things work and to design specific drugs to control diseases, instead of developing drugs by trial and error.

For instance, David Langs of the Medical Foundation of Buffalo once managed to analyze the molecular structure of Gramicidin-A, a bacteria-derived antibiotic. It took him 10 years.

Using the new technique, Nobel co-winner Herbert A. Hauptman's team solved the structure overnight.

Initial studies involve a compound that could shed light on blood pressure problems, but the method could aid researchers working on diseases from diabetes to AIDS.

The new method, which took nearly three years to develop, was to be unveiled in Florida during a meeting of crystallographers. The team from the Medical Foundation of Buffalo and the University at Buffalo described the work done here in analyzing the structure of a complex crystal containing more than 300 atoms.

"It's the first time that a structure of this complexity has been solved by this technique," said Hauptman, leader of the team and co-winner of the 1985 Nobel Prize in chemistry. His Nobel honor was for development of another method for determining the structures of molecules with up to 100 non-hydrogen atoms.

By cutting the time involved in the work and automating part of the process, in what they termed a shake-and-bake approach, the UB scientists hope to spur a wide range of research into the stuff of which humans are made and the viruses that attack their bodies.

"This new technique is something that can be programmed, and anyone can use it," Dr. William L. Duax, research director for the medical foundation, said here Friday. "It can put that tool in people's hands."

Last month, the foundation's Research Institute won a $3 million, four-year federal grant that officials said may make it the key center worldwide for the study of ways to determine the structure of the body's basic construction materials and viruses that attack the body.

The new technique was developed under that program, with funding from the National Science Foundation and National Institutes of Health, and a report in a professional journal has excited researchers nationwide.

"It has surprised the community, that it's working," Duax said.

The technique, along with a more limited chemical procedure now being tested at Johns Hopkins University in Baltimore, offers a way of understanding an elusive range of proteins and other molecules that offer great promise in drug development.

Scientists have studied the structures by analyzing the patterns of X-rays scattered by the molecules and then working backward to determine what the scattering structure must look like. Small molecules can be analyzed with the direct mathematical methods developed by Hauptman and others, and very large molecules can be "solved" by adding heavy mercury or uranium atoms with easily recognized patterns that provide keys to the overall structure.

The mathematical approach involves probabilities that multiply and eventually break down as the molecules get larger, though, while the metal insertion technique distorts smaller structures. The mid-range gap, with its tantalizing possibilities, has eluded most researchers until now.

"For molecules in the range of 200 to 500 atoms, there have not really been satisfactory techniques that can be used routinely, let alone automatically," said senior foundation research scientist Charles Weeks.

"As we get to even larger structures, it'll take longer," Coax cautioned. "But just getting it down to a couple of weeks was a major advance."

The test antibiotic is a helical structure that transports ions, such as sodium and potassium, across body membranes. Imbalances in those ions lead to high blood pressure, and the institute's work will focus on proteins related to that disease, mid-range proteins such as the diabetes-related hormone insulin, and breast cancer.

But the method can be used on all proteins. If scientists can determine the structure of the proteins in the virus that causes acquired immune deficiency syndrome, for example, it may be possible to design drugs to destroy that virus.

The length of time needed to analyze the structures has been a "bottleneck" in programs to develop new antibiotics or drugs that mimic or block the effects of proteins, National Institute of General Sciences program director Dr. John Norvell has said. The new technique, said UB researcher Russ Miller, could cut drug development time from years to weeks.

But there is a drawback: The new method relies on lengthy runs in supercomputers, and "as the procedure becomes more

computationally complex, it becomes more expensive," Columbia University crystallographer Wayne Hendrickson commented in the professional journal Science.

For the test material, the Medical Foundation team short-cut the time problem by using human insight. The computer programs -- which use two supercomputers running parallel -- generated hundreds of thousands of random molecules, which scientists then narrowed down to a smaller sample that they thought was most likely to lead to a solution.

The programs then "move" the individual atoms in the

mathematically modeled molecules hundreds or thousands of times, until they stabilize and produce potential solutions. The potential solutions then are turned over to a crystallographer, who uses visualization tools and refinement techniques to pinpoint the correct molecular structure.

Although the computer run for Gramicidin-A was only an overnight operation, developing the solution strategy took three months.

Herbert A. Hauptman: "Solving" structures may take

only weeks.

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