Until recently, the application of molecular evolution in the laboratory had been limited to display technologies involving biological molecules, where small molecules lead discovery was considered beyond this biological approach. DELs have opened the field of display technology to include non-natural compounds such as small molecules, extending the application of molecular evolution and natural selection to the identification of small molecule compounds of desired activity and function.
DNA encoded chemical libraries bear resemblance to biological display technologies such as antibody phage display technology, yeast display, mRNA display and aptamer SELEX. In antibody phage display, antibodies are physically linked to phage particles that bear the gene coding for the attached antibody, which is equivalent to a physical linkage of a “phenotype” (the protein) and a “genotype” (the gene encoding for the protein ). Phage-displayed antibodies can be isolated from large antibody libraries by mimicking molecular evolution: through rounds of selection (on an immobilized protein target), amplification and translation.
In DELs the linkage of a small molecule to an identifier DNA code allows the facile identification of binding molecules. DELs are subjected to affinity selection procedures on an immobilized target protein of choice, after which non-binders are removed by washing steps, and binders can subsequently be amplified by polymerase chain reaction (PCR) and identified by virtue of their DNA code (e.g.by DNA sequencing). In evolution-based DEL technologies hits can be further enriched by performing rounds of selection, PCR amplification and translation in analogy to biological display systems such as antibody phage display. This makes it possible to work with much larger libraries.