DNA Bar Codes For Libraries | August 10, 2009 Issue - Vol. 87 Issue 32 | Chemical & Engineering News
Volume 87 Issue 32 | p. 31 | Concentrates
Issue Date: August 10, 2009

DNA Bar Codes For Libraries

Methods have screened 800 million compounds for kinase inhibitors
Department: Science & Technology
Keywords: DNA-encoded, small-molecule library, enzyme inhibitor
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The sequence of a DNA tag identified attached small molecules in an 800 million-member chemical library.
Credit: Adapted from Nat. Chem. Biol.
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The sequence of a DNA tag identified attached small molecules in an 800 million-member chemical library.
Credit: Adapted from Nat. Chem. Biol.

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.

 
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