Edition: U.S. / Global

Trying to Design Brand New Drugs By Supercomputer

Published: November 7, 1995

THE goggle-wearing scientists sat staring at a movie screen as 3-D images danced before their eyes. One munched on popcorn, another on a candy bar. Unmindful of movie theater etiquette, they chattered excitedly among themselves. "What if we put a carbon atom here?" one suggested. "How about an oxygen there?" said another.

This was not Friday night at the movies. Nor were the scientists watching videos of those wildly popular 3-D movies of the 1950's. Rather, the subject of their rapt attention was a molecule they had created that might someday become a potent weapon against a currently incurable disease.

The scientists, a chemist, two biochemists and a physicist-biologist at Cornell University here, hope to develop new drugs more systematically than the traditional approaches that involve either luck or the laborious screening of tens of thousands of compounds.

As one of the scientists, Dr. Steven E. Ealick, put it the other day: "The trial-and-error method of drug development is simply too inefficient. It's like collecting everyone's office keys from the Empire State Building and trying to find the one key that will open a particular door. But if you called a locksmith, you'd be in the door in a matter of minutes."

The approach, known as rational -- or, more precisely, structure-based -- drug design, has been hotly pursued for at least a decade by scientific teams both in research institutions and in drug companies. The Cornell team is a relative newcomer to the field, having plunged in about five years ago. Its interest was spurred by a $3.3 million grant from the National Institutes of Health and ready access to what Cornell describes as the world's most powerful X-ray machine and computer.

Although none of the teams have yet produced a clinically useful drug, the Cornell group describes the progress to date as "surprisingly successful" in producing the fundamental data about protein structures needed to design potent new medications.

Like others working on structure-based drug design, Dr. Ealick and his colleagues try to be molecular locksmiths: they devise chemical keys, but ones designed to fit and jam locks, not to open them. The locks are usually the enzymes needed by disease organisms, like those of AIDS and African sleeping sickness.

"Within five years, a lot of protein structures were determined and several potential inhibitors have been designed," said Dr. Ealick, a biochemist at Cornell's New York State College of Agriculture and Life Sciences. So far, though, the AIDS virus has managed to outwit them all by undergoing mutations that change it just enough to render it resistant to the specially designed drugs.

But the approach continues to hold great promise, if not for AIDS -- an effort still being vigorously pursued -- then for other diseases that have defied the usual methods of drug development, including many cancers against which chemotherapy has thus far been ineffective.

"This is still a field in progress," Dr. Ealick said. "On a scale of 1 to 10, we're at about 5. It's one of those things that makes so much sense. We know we can do it, but we're just learning the rules of the game."

One of his projects involves an enzyme critical to the health of T cells, the cells of the immune system involved in rejecting foreign tissue, like cancers and transplanted organs. The enzyme, purine nucleoside phosphorylase, or P.N.P., cleans up metabolic debris that would otherwise build up inside the T cells and shut them down. Sometimes, Dr. Ealick explained, T-cell inactivation is just what is needed, for example, to prevent rejection of transplanted organs or suppress the attack on body tissues that occurs in autoimmune diseases like rheumatoid arthritis and type I diabetes.

"If we could make an inhibitor to this enzyme, we should be able to suppress T-cell response without totally eliminating it," he said. He and his colleagues have analyzed the molecular structure of the enzyme's active site that allows it to pick up metabolic debris. Next they will try to design a substance similar enough to slip right into the spot but so tight fitting that it will jam the enzyme's operation.

Three assets have made Cornell a unique center for a more systematic approach to drug development. Buried beneath a field on the university's sprawling campus is the world's most powerful X-ray machine, the Cornell High-Energy Synchrotron Source, or Chess. The device makes it possible to see easily and rapidly the structure of crystallized molecules, including the proteins involved in disease.

Second, Cornell's Theory Center is home to the world's fastest supercomputer, which enables researchers to analyze quickly the vast amounts of data generated by X-ray crystallography and to produce three-dimensional computer images of the molecules under study.

The third attraction that prompted Dr. Ealick to join Cornell's faculty in 1991 was the "constellation" of people who had the interest and skills needed to pursue structure-based drug design. They include Dr. P. Andrew Karplus, a biochemist, Dr. Bruce Ganem, a chemist, and Dr. David Shalloway, a physicist turned biologist.