DNA Bar Codes For Libraries

A research team led by Barry A. Morgan of GlaxoSmithKline has synthesized and screened a DNA-encoded library of 800 million small molecules to identify enzyme inhibitors (Nat. Chem. Biol., DOI: 10.1038/nchembio.211). Not only does the new method offer an unusually large library size for small-molecule screening, but it's also fast and relatively inexpensive, requiring less than 1 mg of target protein. Each small molecule, which consists of four chemically diverse building blocks, is attached to a unique DNA bar code that, upon sequencing, reveals the molecule's chemical composition. Starting with a short covalently linked double-stranded DNA "headpiece," the researchers constructed the library with four rounds of chemical synthesis, ligating a specific sequence of duplex DNA to the headpiece for each chemical building block added to the other end. Three rounds of affinity selection with the 800 million-member library and high-throughput sequencing of DNA tags revealed potential p38 MAP kinase inhibitors. "We believe that this technique could revolutionize the discovery of small-molecule modulators of biological targets," the researchers write.