DNA-encoded libraries (DELs) are a powerful tool for drug discovery that combines the diversity of combinatorial chemistry with the power of DNA technologies. In this blog, we will explore the structure, screening process, and capabilities of DELs, with a focus on their application in chemical biology and drug discovery.
Structure of DNA-encoded libraries
DELs consist of small molecules, typically less than 500 daltons, that are conjugated to DNA oligomers through a linker. The resulting DNA-encoded small molecules (DESMs) are pooled together to form a library containing millions or even billions of unique compounds. Each DESM is tagged with a unique DNA sequence, which serves as a “barcode” that can be used to distinguish one compound from another. The barcode also allows for the facile amplification and sequencing of the DESMs, enabling large-scale screening.
Screening process of DNA-encoded libraries
The screening process for DELs involves the incubation of the compound library with a target protein of interest. The aim of the screening is to identify DESMs that bind to the target with high affinity and selectivity. Once the screening is complete, the DESMs that have bound to the target are isolated and the corresponding DNA barcodes are sequenced. The resulting sequences are then mapped back to the original library to identify the specific compounds that have bound to the target. By screening a large DEL, it is possible to identify multiple hits in a single experiment.
Capabilities of DNA-encoded libraries
The use of DELs has numerous advantages in drug discovery and chemical biology. Firstly, the diversity of compounds that can be synthesized and screened using DELs is huge, making it more likely that unique, potent compounds can be identified. Secondly, the barcoding system of DESMs allows for efficient and cost-effective screening of large libraries. Thirdly, DELs can be used for target identification and validation, as well as hit identification. Fourthly, DELs are highly flexible and can be used for a wide range of target classes, including challenging targets such as protein-protein interactions.
Conclusion
In conclusion, DNA-encoded libraries are a powerful tool for drug discovery and chemical biology that offer numerous advantages over traditional screening methods. The structure of DELs, which consists of small molecules conjugated to DNA oligomers, allows for the facile amplification and sequencing of compounds. The screening process involves incubation of the library with a target protein, followed by identification of the corresponding binders and their subsequent amplification and sequencing to identify the specific hits. The capabilities of DELs include the identification of unique and potent compounds, efficient and cost-effective screening, target identification and validation, and the screening of challenging targets. With these benefits, DNA-encoded libraries are poised to play an increasingly important role in the discovery of new drugs and therapeutic targets.