DNA‐Encoded Libraries: Towards Harnessing their Full Power with Darwinian Evolution

Abstract

DNA-encoded library (DEL) technologies are transforming the drug discovery process, enabling the identification of ligands at unprecedented speed and scale. DEL makes use of libraries that are orders of magnitude larger than traditional high-throughput screens. While a DNA tag alludes to a genotype-phenotype connection that is exploitable for molecular evolution, most of the work in the field is performed with libraries where the tag serves as an amplifiable barcode but does not allow "translation" into the synthetic product it is linked to. In this Review, we cover technologies that enable the "translation" of the genetic tag into synthetic molecules, both biochemically and chemically, and explore how it can be used to harness Darwinian evolutionary pressure.

Navigating a 1E+60 Chemical Space

“…Since the advent of combinatorial chemistry in the early 1990's, which was triggered by the invention of the split-and-mix method yielding one-bead-one-compound libraries of millions of peptide and peptide-like oligomers in a few tens of synthetic operations, [1][2][3] drug discovery has been fascinated and partly driven by large numbers. [4][5][6] Approaches ranged from the "needle in a haystack" method of high-throughput screening typical for genetically encoded display libraries 7,8 and DNA-encoded libraries, 9,10 to the concept of chemical space guiding the design of focused libraries of small druglike molecules, [11][12][13] fragments 14,15 and peptides. [16][17][18] Many projects are currently exploiting "makeon-demand" virtual libraries of a few billion members obtained by using various coupling chemistries to combine two to four building blocks, each being taken from a pool of thousands of building blocks, to form linear, branched or cyclic oligomers.…”

Expanding Bioactive Fragment Space with the Generated Database GDB-13s

“…Medicinal chemistry becomes an increasingly retrospective activity as public databases such as PubChem and ChEMBL list increasing numbers of known drug-like molecules and their biological activity, from which new analogues can be derived. Nevertheless, introducing chemical novelty in new drugs is important because it can help to address new target types and overcome the limitations of classical molecular series in terms of physicochemical properties, selectivity, toxicity, and metabolism, as well as to secure intellectual property and the possibility of commercial development. − Currently, innovation focuses on exploiting very large libraries of screening compounds obtained by combining known building blocks using known chemistry. , These libraries contain billions of molecules, as in ZINC or the Enamine REAL database, , up to hundreds of billions of molecules in DNA encoded libraries, − or even much larger numbers of peptides and cyclic peptides in phage or ribosome display libraries. , Such molecules often break Lipinski’s rule of five but can nevertheless be developed as drugs. , …”

“… 3 − 6 Currently, innovation focuses on exploiting very large libraries of screening compounds obtained by combining known building blocks using known chemistry. 7 , 8 These libraries contain billions of molecules, as in ZINC 9 or the Enamine REAL database, 10 , 11 up to hundreds of billions of molecules in DNA encoded libraries, 12 − 15 or even much larger numbers of peptides and cyclic peptides in phage or ribosome display libraries. 16 , 17 Such molecules often break Lipinski’s rule of five but can nevertheless be developed as drugs.…”