Using DNA-encoded libraries of fragments for hit discovery of challenging therapeutic targets

ABSTRACT

Introduction

The effectiveness of Fragment-based drug design (FBDD) for targeting challenging therapeutic targets has been hindered by two factors: the small library size and the complexity of the fragment-to-hit optimization process. The DNA-encoded library (DEL) technology offers a compelling and robust high-throughput selection approach to potentially address these limitations.

Area covered

In this review, the authors propose the viewpoint that the DEL technology matches perfectly with the concept of FBDD to facilitate hit discovery. They begin by analyzing the technical limitations of FBDD from a medicinal chemistry perspective and explain why DEL may offer potential solutions to these limitations. Subsequently, they elaborate in detail on how the integration of DEL with FBDD works. In addition, they present case studies involving both de novo hit discovery and full ligand discovery, especially for challenging therapeutic targets harboring broad drug–target interfaces.

Expert opinion

The future of DEL-based fragment discovery may be promoted by both technical advances and application scopes. From the technical aspect, expanding the chemical diversity of DEL will be essential to achieve success in fragment-based drug discovery. From the application scope side, DEL-based fragment discovery holds promise for tackling a series of challenging targets.

KEYWORDS:

• DNA-encoded library
• fragment-based drug discovery
• hit discovery
• encoded self-assembly
• dynamic combinatorial library

Article highlights

• The DNA-encoded library (DEL) technology is a powerful high-throughput drug discovery platform that significantly enhances the capabilities of fragment-based drug discovery (FBDD).

• Leveraging its huge library size and DNA’s ability to hybridize, the encoded self-assembling chemical (ESAC) library facilitates the discovery of chemical fragments through fragment display.

• By allowing reversible and dynamic assembly, the dynamic DELs and PNA/DNA-directed libraries enhance the discovery of fragment synergy.

• Through the development of target-templated in situ chemical conjugation, DEL expedites the identification of full ligands and simplifies the fragment-to-hit optimization.

• The integration of DEL and FBDD may significantly promote the hit discovery of challenging therapeutic targets, particularly those with extended target-drug binding interfaces.

• Future opportunities of fragment-based DELs lie in the continuous expansion of library chemical diversity and the application scope of therapeutic targets.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China (92353303, 22222702 and 22361162605) and the Fundamental Research Funds for the Central Universities (2022CDJQY-001) awarded to Yizhou Li. It is also supported by the National Natural Science Foundation of China through grant 22107016 awarded to Gong Zhang, and grant 22107017 awarded to Yangfeng Li.