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Brad Anderson & Tian-Xiang Xiang
Streamlining Drug Design

by Jeff Worley & Robin Roenker

The high cost of prescription drugs is a hot-button issue today. Patients protest that their medications are unaffordable, while pharmaceutical companies insist that the cost of years of research—and hundreds of failed drugs along the way—must be factored into prescription prices.

Photo of Tian-Xiang Xiang (left) and Brad AndersonOne means of easing the debate may ultimately lie in computer-assisted drug design. Its premise: initially narrow the field of potential new drugs computationally, allowing only the most promising ones to enter laboratory testing. It's a process that could vastly streamline drug development, thereby lowering the cost to produce—and potentially, to buy—new prescription medications.

Professors of pharmaceutical sciences Brad Anderson and Tian-Xiang Xiang have collaborated in utilizing computers to predict the developability and delivery properties of drugs since the early 1990s. The computational methods being employed by these researchers can assist in the design of new molecules and in testing existing compounds for their efficacy and potential to be developed into marketable drugs.

Anderson and Xiang have been particularly interested in studying membrane transport—the process by which a molecule gains entrance to a cell through its membrane—as a measure of its delivery potential. After all, unless the drug can successfully cross membranes, it will never be absorbed into the bloodstream after a patient ingests a tablet, nor will the drug enter the targeted cells.

Yet the inner workings of the membrane transport mechanism are somewhat mysterious, since experimental observations do not allow one to directly observe the molecules moving within the membrane. "All we see in a transport experiment is what we have on one side of the membrane, and the rate at which it gets to the other side," Anderson says. But by utilizing molecular dynamics simulation, driven by many hours of computation on the university's supercomputer, Anderson and Xiang have been able to simulate a rare, albeit virtual, peek at how membrane transport works.

"Even though a membrane is very thin, only 30 or 40 angstroms thick, it is a very complex barrier, consisting of multiple domains. The molecular dynamics simulation allows us to watch the molecules as they partition into the membrane and diffuse through these various regions. They tumble. They rotate. They prefer certain regions of the membrane to others," explains Anderson.

Informed by their simulations, as well as specialized theory and equations they've developed to describe these processes, Anderson and Xiang are making progress in computationally predicting the likelihood that a given drug will effectively transport across a membrane. Those drugs that can cross within a desirable time frame may warrant further lab testing.

Anderson and Xiang are also exploring the use of molecular dynamics simulation to test drug stability in "amorphous solid-state matrices." Eventually the pair hopes to be able to computationally predict a drug's stability either in tablets or other solid dosage forms. In doing so, they may be able to avoid the lengthy process of manufacturing and conducting long-term stability studies of compounds that are unlikely to be stable in a given formulation.

About Brad Anderson and Tian-Xiang Xiang

Brad Anderson and Tian-Xiang Xiang have collaborated since the early 1990s, when they were colleagues at the University of Utah. They joined the UK faculty in 2000. With Xiang's expertise in computation, and Anderson's in experimentation, the pair has the advantage of being able to "go back and forth between the computer and the experiment," Anderson says.

Anderson and Xiang Research Team