Eric Bennett sits in his office wearing 3-D glasses and staring at a computer monitor. Dressed in a T-shirt, shorts, and athletic shoes, he could be mistaken for a graduate student taking a break by playing a computer game in which red, white, purple, and blue objects seem to jump off the screen like magic. But Bennett isn’t playing. He’s an associate professor and assistant director of the University of Minnesota’s Center for Drug Design (CDD), and those multicolored objects are molecular models that could hold the key to developing new, life-saving drugs.

A chemist can come up with a molecule that is very activein the test tube, but it doesn’t necessarily mean that, as a drug in the body, it’s going to reach its target protein,” Bennett explains.

“We use the computer to construct a model of the molecule that is approximately the right shape to fit into the protein. Out of thousands of possible matches, the computer can find and test about 100 molecules and narrow those down to five that are extremely similar. We then look at the structures of those five molecules on the screen and use them as starting points.”

This type of computer modeling can save precious time and money in the race to discover new drugs, says Bennett, who, as a computational chemist, supports all of the drug research teams at the CDD.

Using novel and innovative approaches to drug design in multidisciplinary laboratories is the primary purpose of the CDD, the only center at an American university devoted exclusively to innovative drug discovery and design. It was founded in 2002 and continues to be funded by the income from royalties received from Carbovir, the basis for the first drug ever designed specifically to target HIV/AIDS. The Carbovir compound, discovered in 1987 by University Professor Robert Vince and his research associate Mei Hua, is known commercially as Ziagen and sold worldwide by GlaxoSmithKline.

Up one flight of stairs from Vince’s office in Weaver-Densford Hall is the long, narrow laboratory where, in 1987, Vince asked Hua, then a visiting scientist from China, to prepare a series of five compounds he thought would be good candidates for targeting HIV. The incidence of the virus that causes AIDS had increased exponentially since it was first reported in the United States in 1981, and a call had gone out from the Food and Drug Administration asking pharmaceutical companies and labs to test their inventories of unassigned drugs against the virus. The hope was that one might prove effective against the disease that was quickly becoming an epidemic.

Vince took a different approach. He and Hua concentrated their efforts on designing an entirely new drug. In only six months, Hua had completed and tested the compounds and Carbovir was confirmed by the National Institute of Health (NIH) as a vast improvement over AZT, a drug originally prepared as an anticancer compound in the 1960s. Vince and Hua’s research notes from 1987 showing the final experiment in the synthesis of Carbovir are now etched on the University’s Wall of Discovery on the Scholars Walk that bisects the Minneapolis campus.

“It’s very unusual for a drug candidate from a small academic laboratory to make it through the highly competitive pharmaceutical development process to the point of becoming a new commercial drug,” Vince says. “It costs hundreds of millions of dollars from discovery to the market. Unlike academia, the drug companies have the money, the chemists, and the labs to do this. But, in 1987, there was an urgent need for an HIV/AIDS drug, and we were ready to come up with one.” Now, with the establishment of the CDD and its focused, multidisciplinary research groups, Vince is confident that they can do it again—without the problems that arose from the licensing of Carbovir.

In 1988, the University patented Carbovir and licensed it to Glaxo—and then the long wait for royalties began. Glaxo claimed that Ziagen per se was not covered by the patent, and a lawsuit ensued between the University and the giant pharmaceutical company. It wasn’t until 1999 that a settlement in favor of the University was reached.

Vince’s voice softens when he talks about the lawsuit. “This was the worst thing that ever happened in my career,” he admits. “It was very depressing. While we spent years trying to prove that we owned the intellectual property for this compound, six or seven other HIV/AIDS drugs came on the market—even though our discovery was the first and could have been helping people.”

But the settlement also turned out to be the best thing that ever happened in Vince’s career, because the royalties from the drug—approximately $45 million annually and $300 million over the life of the patents—made it possible for him to found the CDD. Affiliated with the University’s Academic Health Center, the CDD now employs 40 scientists and administrators who are divided into five research teams, each with several drug design projects under way, including to target tuberculosis (TB), Parkinson’s, Alzheimer’s, leukemia, HIV/AIDS, and Hepatitis C, plus an antidote for cyanide poisoning and an improved drug for sun protection.

Courtney Aldrich, associate director and a principal investigator at the CDD, spends most of his time writing grant proposals and manuscripts for publication, communicating with colleagues around the world, and weaving his way through the labyrinth of laboratory equipment to oversee the many TB-related projects his team of chemists, biochemists, and microbiologists is working on. “It’s been 40 years since a new drug was developed for TB,” Aldrich says. “In the meantime, multi-drug-resistant strains of this disease have developed into the world’s leading cause of death from bacterial infection.”

Aldrich’s team is in the final year of a three-year NIH grant, and he is optimistic that they’ll be successful. “My team is rapidly moving forward on creating a potent molecule that could break through the barrier of the micro-bacteria containing the protein that causes these strains,” Aldrich says. “And the competition to achieve this is a powerful motivator. We have a small team, so we can be innovative and stay focused.”

Developing drugs wasn’t Vince’s goal when he came to the University in 1967 to teach medicinal chemistry to pharmacy students and conduct research. But much has happened in the interim. Vince was recently honored by the American Chemical Society, which installed him in its Hall of Fame, for his 35 years of innovative and imaginative contributions to the technology of drug design and his creation of the CDD.

In addition to establishing the CDD, Ziagen royalties were also used to establish the Robert Vince Endowed Chair in Medicinal Chemistry. The chair was intended for Vince, but he turned it over to the College of Pharmacy on the proviso that it be used to recruit a world leader in the field. The chair is currently held by Gunda Georg, who came from the University of Kansas and is now head of the Department of Medicinal Chemistry. And when the CDD was founded five years ago, an endowment was established to make the center self-sustaining when the Ziagen royalties taper off in a few years.

“In this way,” says Vince, “we can continue developing cutting-edge drugs to help alleviate human suffering around the world.”