Duke University researchers have developed a technique that they say can capture the many states of an RNA molecule and screen hundreds of thousands of potential drug candidates.
"When it comes to targeting RNA, the devil is in the details, and the details are in the dynamics," said Hashim M. Al-Hashimi, Ph.D., James B. Duke Professor of Biochemistry and Chemistry at the Duke University School of Medicine.
Al-Hashimi and his team showed that their technique can pick compounds with anti-HIV activity out of a line-up of 100,000 that do not in an article in Nature Structural and Molecular Biology published today.
"This could present a new paradigm for drug discovery," explains Al-Hashimi. "Almost every drug is designed to target proteins. By making it possible to accurately target RNA, we are opening the field up to new and potentially life-saving discoveries."
According to Al-Hashimi, drug discovery efforts over the last fifty years have overlooked nearly all "non-coding" RNAs. One clear reason for this glaring omission is the fact that RNA is one of the most flexible, dynamic molecules around. It doesn't have the typical nooks and crannies that drug developers use to target proteins, and even if it did, a given RNA probably wouldn't sit still long enough for a scientist to capture it on film.
"This is a long-standing problem," says Al-Hashimi. "The motion of life is in these molecules. But nobody can predict which drugs will bind RNA, in large part because we don't have good movies of them." Most methods that guide the discovery of drugs either rely on a still image captured in the laboratory that doesn't show the molecule in action, or movies generated on a computer that are based on calculations, not real data.
In the study, Al-Hashimi and his team took 78 compounds known to bind that same RNA target from HIV and added them to a chemical library of 100,000 compounds that they had shown incapable of binding. When they used their technique to screen all the compounds, they were able to pull out the 78 with known anti-HIV activity.
"The key in this study is that we know whether the drugs bind or not, which gives us a means to evaluate how accurate the shapes of our RNA are," said lead study author Laura Ganser, a graduate student in Al-Hashimi's lab. "Since it performed so well, we feel that the shapes are accurate, so now we can find and design new drugs."
Image: "Movies" made with nuclear magnetic resonance capture the dynamics of an RNA from the HIV-1 virus. The revealed shapes can lead to new drug targets. Image courtesy of Yu Xu, Laura Ganser, Megan Kelly, Hashim M Al-Hashimi, Duke University.