Transforming Drug Discovery: DNA-Encoded Chemical Libraries
DNA-encoded chemical library (DECL) is a novel and understudied tool that facilitates the synthesis and screening of vast collections of small molecule compounds on promising scales and it is already utilized by the pharmaceutical industry and in medicinal chemistry to merge the fields of combinatorial chemistry and molecular biology, with the objective to accelerate the drug discovery process.
DECL technology works by attaching chemical compounds or building blocks to short DNA fragments, which act as identification barcodes and sometimes also direct and control the chemical synthesis. This technique allows for the large-scale creation and examination of libraries via affinity selection, typically using an immobilized protein target. A new homogeneous method for screening DNA-encoded libraries (DELs) has been developed, employing water-in-oil emulsion technology to isolate, count, and identify individual ligand-target complexes in a single-tube approach.
The synthesis of a DECL initiates with an oligonucleotide containing a chemical linker moiety and proceeds through iterative cycles of DNA barcode elongation and chemical synthesis. Due to the minimal amounts of protein, little assay development, and no specialized instrumentation DECL selections allow for parallel runs with different conditions in a similar manner to protein crystallization process.
The fact that DECL does not need biochemical assays for binder identification unlike conventional screening methods such as high-throughput screening allows researchers to isolate the binders for a broader range of proteins, including those that are difficult to target with conventional methods. This capability not only facilitates the discovery of target-specific molecular compounds but also provides access to binders for pharmacologically important yet previously “undruggable” target proteins, opening new avenues for developing drugs for previously untreatable diseases. By eliminating the need to initially assess the activity of hits, DECL technology is expected to identify many high-affinity binders that will be confirmed as active in subsequent analyses, thereby providing an efficient method for discovering high-quality hits and pharmaceutical leads.
One of the challenges that lies ahead to form a reliable and useful DECL tool is gathering building blocks which can be solved via a form of trade between laboratories and institutions or parallel synthesis of new building blocks. Additionally, the impurity of these samples makes it difficult to analyze the data, and the selections can be limited to soluble purified proteins and not the cell surface displays and intracellular targets. In any case, it is a field with high potential and there are very active research groups that are constantly investigating and improving on these challenges, and it gives an interesting research opportunity to young researchers.
The automated dosage system (ADoS) that is developed for the parallel automated purification of libraries. (Image from https://doi.org/10.1021/acsomega.2c02906)
Reference:
https://pubs.acs.org/doi/10.1021/acsomega.2c02906
Satz, A.L., Brunschweiger, A., Flanagan, M.E. et al. DNA-encoded chemical libraries. Nat Rev Methods Primers 2, 3 (2022). https://doi.org/10.1038/s43586-021-00084-5