DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences

Abstract

DNA-encoded compound libraries are a highly attractive technology for the discovery of small molecule protein ligands. These compound collections consist of small molecules covalently connected to individual DNA sequences carrying readable information about the compound structure. DNA-tagging allows for efficient synthesis, handling and interrogation of vast numbers of chemically synthesized, drug-like compounds. They are screened on proteins by an efficient, generic assay based on Darwinian principles of selection. To date, selection of DNA-encoded libraries allowed for the identification of numerous bioactive compounds. Some of these compounds uncovered hitherto unknown allosteric binding sites on target proteins; several compounds proved their value as chemical biology probes unraveling complex biology; and the first examples of clinical candidates that trace their ancestry to a DNA-encoded library were reported. Thus, DNA-encoded libraries proved their value for the biomedical sciences as a generic technology for the identification of bioactive drug-like molecules numerous times. However, large scale experiments showed that even the selection of billions of compounds failed to deliver bioactive compounds for the majority of proteins in an unbiased panel of target proteins. This raises the question of compound library design.

Generating Multibillion Chemical Space of Readily Accessible Screening Compounds

“…The physico-chemical features of the chemical space generated in this work are similar to those of DNA-encoded libraries ( Kunig et al., 2018 ). In both cases, this is related to the fact that final library members are constructed from at least three building blocks, which increases the lower MW limit.…”

“…In our opinion, the huge size of both DNA-encoded libraries and multibillion chemical spaces like the one described herein can be considered as compensation for the increased molecular complexity (provided that efficient in vitro or in silico screening technologies are available to mine these ultra-large libraries). The success stories available in the literature for both technologies ( Goodnow et al., 2017 ; Kunig et al., 2018 ; Lyu et al., 2019 ; Gorgulla et al., 2020 ) can serve as a justification for the above hypothesis.…”

Towards an Optimal Sample Delivery Method for Serial Crystallography at XFEL

“…HTS employs chemical libraries containing >10 9 compounds which only explores a small fraction of the total chemical space. Fragment-based drug discovery [3] (FBDD) and DNA-encoded libraries (DEL) [4,5] are developed to more efficiently explore the chemical space, either by improving ligand efficiency (FBDD) or increasing the complexity of the chemical library (DEL) during HTS. Both technologies have proven to be revolutionary and demonstrated their power by successfully bringing candidate drugs either to market (for e.g., Vemurafenib, a v-Raf murine sarcoma viral oncogene homolog B1 (B-RAF) kinase inhibitor for the treatment of metastatic melanoma [6]) or to advanced clinical trials (for e.g., GSK2982772, a first-in-class inhibitor of receptor-interacting protein kinase 1 (RIPK1) for chronic inflammatory diseases [7]).…”

Navigating the DNA encoded libraries chemical space

“…Several cycles of affinity selection, typically involving an immobilized target protein and a pool of libraries, yield a mixture of compounds enriched in binders to the protein of interest. Amplification of the DNA region by polymer chain reaction methods and posterior next generation sequencing permits the identification of the structure of the binding molecules [3][4][5][6][7][8] .…”

“…The progress achieved in this field during the last two decades has transformed DEL to a powerful production tool for most pharmaceutical companies to identify new ligands for both novel and traditional biological targets [2][3][4][5][8][9][10][11][12][13] . Despite of this, a remaining challenge for DEL is achieving the right balance of library size and molecular properties.…”