HTS allows researchers to test thousands of small drug-like molecules at once for a specific biological activity, such as inhibiting the cell movements that allow cancer cells to spread in the body. Screening for potential new drug compounds in complex systems differs from the traditional drug discovery approach, which begins with one particular protein of interest and tries to find inhibitors for that specific target.
By starting with many small molecules and screening for a certain biological effect, researchers rapidly pinpoint drug candidates. But that's where chemical genetics hits a wall. Once researchers find an inhibitor, or potential drug, they want to know how it works, by identifying the protein on which the inhibitor acts. But how?
"This is a significant problem for the entire field," Peterson says. "What particular protein is the small molecule hitting to get that biological effect?" In this case, Peterson and his colleagues identified an inhibitor called pirl1, which, when added to cell extracts, blocks the assembly of actin fibers used for cell motility.
The methods scientists typically use to find protein targets only work in certain cases. For instance, if an inhibitor binds tightly to its target, then researchers could use that to pull both the inhibitor and its target protein back out of the cell extract. Pirl1, however, like many small molecule inhibitors, binds to its target only weakly.