That's what the Scripps Research team set out to learn in the new study, which was funded by a grant to the Olson lab from the National Institutes of Health to seek ways to combat drug-resistance in HIV.
To accomplish this goal, the team procured a "library" of 384 compound fragments that had been compiled by a company called Active Sight. Screening fragments rather than larger compounds has become more popular over the last several years, Perryman explained, since using these smaller pieces is a more efficient way to find promising structures than using libraries of large compounds. In addition, fragments can be extended, combined, and modified using "structure-based drug design" in a way that makes them fit tightly into the right binding sites, without displaying the unwanted interactions that sometimes come with larger molecules. Using libraries of much larger, "lead-like" compounds is less efficient, and those large compounds are less extendable.
Since the HIV protease molecule is in constant motion, the team of scientists, which included members of Scripps Research Professor John Elder's lab, first crystallized the molecule in various different conformations. The scientists then screened a library of fragments against these crystals to see if any of them bound and characterized the structural features of the results using the Stanford Synchrotron Radiation Lightsource (SSRL). Stout notes that, in total, the project conducted a massive screen of more than 800 crystals producing more than 400 data sets, a feat made possible by SSRL's robotic capabilities.
In their initial experiments, the scientists met with partial successenough to establish a proof-of-conceptas one fragment attached to the "eye site" between the tip of a flap and the top of the active site's wall. However, the large active site of the molecule tended to be problematic, interfering with the scientists' goal of searching for fragments that bind to alternate
|Contact: Keith McKeown|
Scripps Research Institute