Future challenges with DNA-encoded chemical libraries in the drug discovery domain

ABSTRACT

Introduction: DNA-encoded chemical libraries (DELs) have come of age and emerged to become a powerful technology platform for ligand discovery in biomedical research and drug discovery. Today, DELs have been widely adopted in the pharmaceutical industry and employed in drug discovery programs worldwide. DELs are capable of interrogating drug targets with an extremely large number of compounds highly efficiently.

Area covered: In this review, the authors introduce the history of DELs and provide an overview of the major technological components, including encoding methods, library synthesis, chemistry, selection methods, hit deconvolution strategy, and post-selection data analysis. A brief update on the hit compounds recently discovered from DEL selections against drug targets is also provided. Finally, the authors discuss their views on the present challenges and future directions for the development and application of DELs in drug discovery.

Expert opinion: DELs have provided great opportunities for lead compound discovery at an unprecedented scale and efficiency in drug discovery. The key to the future success of DELs as true discovery modalities, rather than just ‘a way to make many compounds,’ is to go beyond physical binding to functional or even phenotypic assays with the capability to probe the biological system.

KEYWORDS:

• DNA-encoded chemical library
• drug discovery
• high throughput screening
• combinatorial chemistry
• drug targets

Article highlights

• DELs have come of age and become a powerful technology platform for ligand discovery in biomedical and pharmaceutical sciences.

• The major technological components, including encoding methods, library synthesis, chemistry, selection methods, data analysis, and hit identification, have experienced significant advancements in recent years.

• DELs have produced numerous candidate compounds in various drug discovery programs; and it is also possible to perform medicinal chemistry optimization, fragment-based drug discovery, and directed evolution with DELs.

• The many kinds of DEL libraries have rendered this technology great versatility in targeting a large variety of drug targets.

• Selections against complex biological targets and moving beyond binding assays are two important directions for the future development of DELs.

This box summarizes key points contained in the article.

Declaration of interest

The corresponding author, X. Li, is a shareholder of Y-gene Biotech. 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.