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The last post concerned fragment libraries – round built on the philosophy “small fragments can represent massive libraries” at the other end of the scale are DNA encoded combinatorial libraries (DELs).  DELs represent the technological offspring of combinatorial chemistry and molecular biology with a little classical protein biochemistry for good measure. With split pool synthesis to make vast libraries and encoding the sequence of chemistry used in a DNA sequence attached to the compounds, huge libraries can be made and potent ligands identified.  Chromatography with the protein target as ‘bait’ to fish out the most potent compounds followed by PCR to sequence the DNA tag establishes the identity of the best binders.  If you can do affinity chromatography with your protein target, DELs represent the other extreme approach to lead generation.  The first paper is a pure classic – Brenner and Lerner’s PNAS publication contains the essence of the technique in highly readable form.  It contains the brilliant line “we recently, in principle, solved the synthetic procedure for peptides”.   But actually to industrialise takes another 17 years.  There has been a huge number of synthetic chemistry devils to outwit in making the method scalable and Morgan et al’s 2009 paper shows one version of the production and screening of billion compound libraries and the identification of inhibitors reduced to practice.

“Encoded combinatorial chemistry”, Brenner and Lerner,  Proc. Natl. Acad. Sci (1992), 89, 5381-5383

“Design, synthesis and selection of DNA-encoded small-molecule libraries”, Morgan et al, Nature Chem. Bio. (2009), 5, 647 – 654

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