A collection of 800 million chemicals, in which each chemical contains a unique DNA barcode, is used to identify new enzyme inhibitors as reported in a study published online this week in Nature Chemical Biology.
Attaching chemicals to small pieces of DNA is an attractive way of combining the power of molecular biology and chemical synthesis to identify potential drugs. However, this approach for creating "DNA-encoded" chemicals has typically been limited to relatively small collections of chemicals.
Barry Morgan and colleagues have developed a new approach for making DNA-encoded chemical libraries that uses double-stranded, rather than single-stranded, DNA. The authors synthesized chemical libraries nearly 10 times larger than any previous DNA-encoded library and about 5 orders of magnitude larger than typical libraries. In contrast with previous studies, which largely identified chemicals that bound to but did not necessarily inhibit a target, these libraries were used to identify highly effective new inhibitors of kinase enzymes.
With the achievement of library sizes exceeding those of the high-throughput screening libraries typically used at pharmaceutical companies, this method opens up a new and potentially more effective way to hunt for drug leads.