Simulations Find Possible HIV Achilles’ Heel

Molecular dynamics simulations spot alternative drug target

A blindside attack on HIV-1 protease might just combat drug-resistant strains of HIV, according to simulations run by researchers at the University of California, San Diego. When the simulations shut down an exposed movement on the side of the enzyme, the active site shut down as well. The work was published in Biopolymers in June 2006.


A new target for anti-HIV drugs may be the allosteric grooves on the side of HIV-1 protease (see gaps in the middle of the right and left sides). When those are pinched together (see green protein, right and left sides), the flaps over the active site (top) can open. The flaps remain closed when the groove is propped open (red and orange versions). Courtesy of Alexander Perryman.HIV-1 protease is an indispensable worhorse of the HIV virus: It cuts viral protein chains into building blocks ready for assembly into new virus particles. Many of today’s anti-HIV drugs target this enzyme, generally by plugging up its active site and permanently closing two flaps over that area. In HIV strains resistant to these drugs, HIV-1 protease developed flaps that are harder to latch shut. So now some researchers are suggesting targeting flap movement instead of (or in addition to) the active site.


That’s why Alexander Perryman, PhD, now a postdoctoral fellow at California Institute of Technology, Andrew McCammon, PhD, professor of theoretical chemistry and pharmacology at UCSD, and their coworkers were very curious when they noticed an interesting movement on a side surface of HIV-1 protease in molecular dynamics simulations performed in 2004. When the protease closed its flaps across the active site, a groove on the peripheral surface expanded. Conversely, as the active site flaps opened, that same groove, called the allosteric groove, shrunk. It looked as if the movements were directly linked.


So the researchers hypothesized that inhibiting the movement of the allosteric groove would inhibit the movement of the active site flaps as well. In simulations that invoked an imaginary force or drug acting on the allosteric groove, they found their hypothesis was correct. When the allosteric groove is propped open by an imaginary drug, the flaps that guard the active site stay closed. And when the groove is pinched together slightly, these flaps will open.


It is still entirely unknown whether an actual drug exists, or could be created, that would apply the same force as the imaginary drug in the UCSD simulations. Celia Schiffer, PhD, associate professor of biochemistry and molecular pharmacology at the University of Massachusetts Medical School, thinks the groove movements are important for protease function, yet she is not convinced that the allosteric groove is a viable drug target. “I think practically that would be a very difficult place for inhibitors to bind in a specific and high-affinity manner.” But Carlos Simmerling, PhD, associate professor of chemistry at State University of New York, Stony Brook, is impressed by the UCSD strategy of finding a new drug target by observing enzyme movement. “The idea of targeting the mechanism is a lot more powerful than targeting the shape of the binding pocket, which is what current drugs do,” he says.



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