Developing Drugs to Fight Addiction and Disease
What better way to treat cocaine addiction than to develop a drug that could destroy cocaine within the bloodstream almost immediately, before it has a chance to reach the central nervous system and take effect in the addict's body.
Chang-Guo Zhan, an associate professor of pharmaceutical sciences, has made impressive advances toward development of just such a drug. With high-performance computations, including molecular dynamics simulations, powered by parallelized computing clusters, Zhan has gained a more detailed understanding of how a particular well-known protein, called butyrylcholinesterase, or BChE, metabolizes cocaine. In turn, the simulations have helped him envision how best to alter the structure of BChE to hydrolyze cocaine more quickly.
"Our goal is, through changing the BChE structure, to make its activity much higher, which means that if we inject the protein into the blood, the cocaine would almost immediately be destroyed," Zhan says. "With molecular dynamics simulations and high-performance computing, we can see how the protein should be changed to react better with the cocaine. Then, we can design that altered structure computationally."
On its own, BChE can metabolize cocaine within 45 to 90 minutes, but by altering the structure of the protein, in computer simulations Zhan has been able to reduce that metabolism time to only 9 to 18 secondsa speed that should be sufficient to keep the drug from reaching the central nervous system. He's confident with the computational predictions, so he's begun conducting laboratory-based experimental studies with the altered BChE protein, for which he's pursuing a patent.
In addition to his work with cocaine addiction, Zhan is also interested in development of a novel anti-HIV/AIDS drug. Again, computer modeling is key: with high-performance computation, Zhan and associates have simulated the fundamental mechanism by which the HIV virus interacts with and infects a cell.
"The HIV virus has a key protein on the surface, GP120, which can interact with a protein called CD4 on your body's cell to initialize the HIV virus infection," Zhan explains. "So, if we can better understand this protein-protein interaction, we can work to design ways to block the interaction and prevent the virus from entering the cell. It has recently been reported that a compound from green tea can prevent the HIV virus infection, but the required concentration of the compound would be too high to use for humans. Our modeling and simulations have led to an understanding of how the compound can block the interaction between GP120 and CD4. Now we need to design a more potent compound, as a possible next-generation anti-HIV virus drug, to block this initial step of the HIV virus infection. It's a very interesting challenge, because we don't know yet if any compounds can be more potent to do that."
Zhan's other research interests include developing drugs for anti-cancer and anti-inflammation applications, and to treat a wide array of disorders, such as Alzheimer's disease and erectile dysfunction. While Zhan's focus is on computational drug design, he joined UK's College of Pharmacy in 2003 because it is one of the few in the nation where drug design, delivery, and analysis can be implemented at the same location. "I can easily collaborate with colleagues here to test my predictions in the lab."
About Chang-Guo Zhan
Chang-Guo Zhan has dual doctorate degrees in chemistry and in molecular physics. Before joining the UK faculty in 2003, he was a research scientist at the Columbia University Department of Medicine and a visiting scientist at Pacific Northwest Laboratory.
Zhan Research Team