Scientists Develop Method to Screen Large Compound Libraries

A new method to screen libraries of 10 million or more compounds has been developed by scientists from Scripps Florida and the University of Texas Southwestern Medical Center. The new technique uses several million beads, each of which displays a unique ligand. An antibody attached to the target protein is covered with iron oxide particles, which acts as magnetic dust. If the peptoid ligand is legitimate and attaches to the protein, it can be pulled from the mass by using a magnetized centrifuge.

The selected compounds are then removed from the beads through a cleaving process and attached to glass microarray slides. These arrays are mixed with different concentrations of the target protein, allowing the affinity strength of each compound on the array to be determined quickly and efficiently, the researchers say.

The study is published in Chemistry & Biology. The paper is titled “Seamless Bead to Microarray Screening: Rapid Identification of the Highest Affinity Protein Ligands from Large Combinatorial Libraries.”

“Current methods severely limit the size of the libraries you can screen,” says Thomas Kodadek, Ph.D., professor at the Scripps Research Institute's Florida campus. “If you get 20 hits out of a 100,000 compound library, it's feasible to re-synthesize each of those hits to test which are the most effective. But what if you want to screen 10 million compounds? It takes an impossible amount of time to re-synthesize promising compounds for further study.

“To find the most potent ligands, our new method stands head and shoulders over what is available to researchers today,” asserts Dr. Kodadek. In the study, the team used mixed peptide/peptoid libraries, but the method could be applied to any class of compound, he points out. 

Adoption of this new technique will take time and something of a paradigm shift, he adds. “This technology is relevant to custom libraries that are produced on beads,” Dr. Kodadek explains. “Right now, that probably constitutes five percent of screening going on. My guess, however, is that ratio will change once researchers begin to adopt this new method.”

The new screening technology monitors binding of the bead-immobilized molecule to the target protein. Currently, the most widely used high-throughput screens monitor function of the compound. In addition, not all laboratories currently have the equipment and expertise necessary to make microarrays of small molecules.

“I think our method can revolutionize medicinal chemistry,” says Dr. Kodadek, “but this is only the first step.”