DNA AS A TOOL FOR MOLECULAR DISCOVERY - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 539

Reactive groups

A A

B B

Oligonucleotides
FIGURE 16.3

Linkers

DNA-templated synthesis.

Finally, DTS can also be used as a tool for reaction discovery by evaluating
thousands of combinations of substrates and reaction conditions, including tran-
sition metal complexes, Lewis acids, mild oxidants or reductants, and organic
reagents [42].

16.3. DNA-ENCODED CHEMICAL LIBRARIES

The concept of DNA-encoded library was first proposed by Brenner and Lerner in
1992 [43]. The basis of this concept was the covalent attachment of DNA encoding
sequences to compounds of biological relevance. Hence, DNA sequences designed
to have minimal Watson-Crick base-pairing overlap with each other were used as
amplifiable and identifiable “bar codes” [44] in order to construct large collections
of DNA-encoded compounds by stepwise split-and-pool cycles. The DNA-encoded
chemical libraries could then be classified as single or dual pharmacophore-
containing chemical libraries in which one or two DNA strands were used to
encode synthetic small molecules, respectively. In the “single pharmacophore”
approach, which is also referred to as “DNA display,” the oligonucleotide sequence
directs the library synthesis (Figure 16.7) [45-48]. Hence, a library of single-
stranded DNA (ssDNA) molecules is chemically translated into synthetic com-
pound-DNA conjugates. The DNA library is then split into subpools by hybrid-
ization of 20-base codons to complementary oligonucleotide anticodons that are
immobilized on separate columns (orange, cyan, and pink bars). A distinct chemical
transformation is then carried out on each subpool, resulting in the covalent
attachment of a chemical building block onto the DNA (orange, cyan, and pink
balls). The library is pooled and then split on the basis of the next coding region
(green, brown, and yellow bars) and distinct chemical transformations are carried
out for each subpool. The translated library is then subjected to selection for a
function of interest and the DNA linked to the binder is finally amplified and used
as input for the subsequent round of chemical translation. The entire process is
repeated until the library converges. In this context, Harbury and coworkers were
able to synthesize up to 10 8 peptoids that were eventually used for ligand

selection [45].
In the dual pharmacophore libraries introduced by Neri and coworkers as
“encoded self-assembling chemical” (ESAC), two pharmacophores can simulta-
neously bind to a target protein (Figure 16.8) [49,50]. In a typical experiment, two