The researchers' previous work involved creating "nano-movies" of RNA that capture this dance of shape changes. In this new study, the researchers froze individual "frames" from the nano-movies, each showing the RNA in a different conformation, and subjected each of them to virtual screening. To test the method in the "real world," they first tried it on compounds already known to bind a particular RNA molecule from HIV called TAR.
"We showed that by virtually screening multiple snapshots of TAR, we could predict at a useful level of accuracy how tightly these different compounds bind to TAR," Al-Hashimi said. "But if we used the conventional method and virtually screened a single TAR structure determined by X-ray crystallography or NMR spectroscopy, we failed to predict binding of these drugs that we know can bind TAR."
Next, the researchers tried using the method to discover new TAR-targeting drugs. They screened about 51,000 compounds from the U-M Life Sciences Institute's Center for Chemical Genomics. "From this relatively small compound library, we ended up identifying six new small molecules that bind TAR and block its interaction with other essential viral molecules," Al-Hashimi said.
What's more, one of the six compounds, netilmicin, showed a strong preference for TAR.
"Netilmicin specifically binds TAR but not other related RNAs," said former graduate student Andrew Stelzer. "We were very pleased with
|Contact: Nancy Ross-Flanigan|
University of Michigan