DNA-encoded Compound Libraries

Introduction of DNA-encoded Compound Libraries

In recent decades, DNA-encoded chemical library (DEL) has emerged and become a technology platform harnessing the advantages of both biological display libraries and chemical libraries. In a DEL, each small molecule is covalently conjugated with a unique DNA tag, serving as the identifier for the chemical structure of the compound; therefore, the entire library can be prepared and selected simultaneously. The selection is usually performed based on the binding affinity with an immobilized protein target. After non-binders are washed away, the binders are eluted from the target under denaturing conditions. Next, the chemical structure of the selected compounds can be decoded after PCR amplification and Next Generation Sequencing (NGS) to read the corresponding DNA barcodes. Due to the high encoding capacity of DNA molecules, the sensitivity of PCR amplification, and the ultra-high-throughput of NGS, DELs can contain hundreds of millions to billions of compounds, and the selection can be rapidly performed at a minute scale. Notably, the availability of low-cost, genomic-scale NGS technology is a key factor for a DEL to become a powerful screening platform. With the ability to incorporate synthetic chemical structures, DELs are more chemically diverse than biological display libraries, while still featuring the chemotype-genotype link; DEL provides a highly efficient approach to explore larger chemical spaces for drug discovery.

Fig.1 The general scheme for the selection of DNA-encoded chemical library (DEL). (Zhao, 2019)

Application of DNA-encoded Compound Libraries

Today, DELs have already been widely adopted by major pharmaceutical companies and employed in numerous drug discovery programs. The recently reported late-stage clinical trials of drug candidates that originated from DELs have showcased the promising perspective of DELs in drug discovery. In 2017, a soluble epoxide hydrolase (sEH) inhibitor as a phase I clinical candidate to treat chronic obstructive pulmonary disease (COPD) was reported; this is the first molecule discovered from the DEL platform to enter clinical testing. Another prominent example is a first-in-class receptor-interacting protein-1 (RIP1) kinase inhibitor, which is currently being tested in Phase II clinical trial for treating psoriasis, rheumatoid arthritis, and ulcerative colitis; notably, the clinical candidate is only different from the initial DEL screening hit compounds by a few atoms. These examples have showcased the potential of DELs in discovering candidate compounds with favorable properties that can be readily progressed into high-quality drugs.

Fig. 2 DNA-recorded library synthesis. (Madsen, 2020)

The DNA-encoded compound library is one of the important methods in drug discovery. Creative Biolabs has been focusing on drug discovery over years and thus accumulated extensive experience. With experienced experts and strong foundations, we are capable of providing our customers with quality-guaranteed drug discovery-related services. If you are interested in our services or you have any other questions, please don't hesitate to contact us for more information.

References

1. Zhao, G.; et al. Future challenges with DNA-encoded chemical libraries in the drug discovery domain. Expert Opin Drug Discov. 2019, 14(8): 735-753.
2. Madsen, D.; et al. An overview of DNA-encoded libraries: A versatile tool for drug discovery. Prog Med Chem. 2020, 59: 181-249.