Biomedical Engineering Reference
In-Depth Information
single-pharmacophore DNA-encoded chemical libraries, the performance of a library
ultimately depends on its design and purity. If libraries can be constructed including
up to billions of chemical entities, the gain in library size and chemical diversity is
often paralleled by an undesirable increase in the average molecular weight beyond
the generally accepted drug-like criteria (following Lipinski's rule of 5) [67,68]. Fur-
thermore, the number of reaction steps performed for library assembly is inversely
proportional to library quality, due to incomplete reactivity of the reactions used in
the split-pool strategy [58]. Eventually, single-pharmacophore libraries generated by
the combinatorial assembly of two or three different sets of building blocks and con-
taining up to a few million small-molecules typically display compounds that better
fulfill drug-like requirements and are more suitable for further medicinal chemistry
optimization steps (Figure 11.20).
In contrast to single-pharmacophore libraries, large dual-pharmacophore collec-
tions can easily be generated with unrivaled purity by self-assembly of relatively
small DNA-encoded sublibraries (i.e., 10
3
to 10
4
member) [63]. The dual display of
two independent chemical moieties on the distinct extremities of the double-stranded
oligonucleotide (see Figure 11.16, Section 11.2.3) may enable the simultaneous
engagement of adjacent nonoverlapping binding pockets (or clefts) on the same
target protein [93]. In analogy to fragment-based drug discovery approaches, the
individual moieties must be reformatted into a single organic molecule by means of
appropriate linkers and linking chemistry [63,64,94,95].
Last but not least, DNA-encoded chemical libraries are particularly appealing
for the optimization (affinity maturation) of previously discovered lead binding
molecules. Recently, lead-based DNA-encoded libraries have been used for the iden-
tification of compounds with
10,000-fold improved potency with respect to the
parental compound and exquisite selectivity toward the selected target protein [62].
Application of such libraries to drug discovery is part of the most recent research in
the DNA-encoded chemical library field (see Table 11.1, Section 11.4).
>
11.6 CONCLUSIONS
In conclusion, DNA-encoded chemical libraries are coming of age. Remarkable
developments have been gained rapidly over the last decade. Today, DNA-encoded
chemical libraries hold the promise to revolutionize the way to discover novel lig-
ands, pointing to a future where scientists can design and routinely en masse inter-
rogate millions of chemical compounds, ideally using fully integrated platforms on
which synthetic compounds such as like chemical genes truly evolve through the
selection steps as components of an artificial immune system, which quickly raises
high-specific-binding compounds against profoundly different biomacromolecular
antigens.
While we wait for the first drug candidate in clinical trials stemming from a DNA-
encoded chemical library, several pharmaceutical industrial and academic laborato-
ries have already implemented DEL technologies in various drug discovery research
