A new enthusiasm has been kindled for what is, in principle, an old technique: the use of DNA tags to encode individual organic chemicals within a large “pool” of compounds.
The idea of making and screening large numbers of molecules to screen against biological targets is nothing new. Many readers will recall, not always fondly, the combinatorial chemistry “boom” of the 1990s! It is generally agreed that the combinatorial libraries of that period were sub-optimal, particularly in terms of their physicochemical properties, and so the synthesis of large collections of compounds lost popularity … until recently.
Over the last few years, a new enthusiasm has been kindled for what is, in principle, an old technique: the use of DNA tags to encode individual organic chemicals within a large “pool” of compounds. The sizes of the collections that can be made using so-called “split and mix” techniques are extraordinary: libraries containing hundreds of millions of compounds have been reported. And the first reports of hit compounds being identified for drug discovery programmes have appeared in the literature.
There are still challenges, of course, but as the links below make clear, the use of DNA-encoded libraries is growing, and it seems likely to be a “hot topic” next year in medicinal chemistry.
- Lowe, D. The Boston DNA Encoded Library Conference
- Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-Encoded Chemical Library
- Discovery of Highly Potent and Selective Small Molecule ADAMTS-5 Inhibitors That Inhibit Human Cartilage Degradation via Encoded Library Technology (ELT)
- Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium tuberculosis InhA
- The Discovery of Macrocyclic XIAP Antagonists from a DNA-Programmed Chemistry Library, and Their Optimization To Give Lead Compounds with in Vivo Antitumor Activity
— David Clark, Director of Computer-aided Drug Design and Information Services, Early Discovery
Updated Feb. 18: Check out this recent article in Nature about how medicinal chemists at biopharmaceutical companies are using DNA barcoding and DNA templating to identify and construct compounds.