Alice R. Wong

ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.5c00356

Abstract

DNA-encoded libraries (DELs) have revolutionized hit identification in drug discovery by offering an accessible, versatile, and cost-effective alternative to traditional high-throughput screening (HTS). This perspective analyzes the results of recent DEL technology (DELT) screens (2020−2025) to enable medicinal chemistry programs, focusing on case studies where active series were generated from DEL and distills key learnings and design principles for productive library construction. A notable trend is the productivity of 2-cycle DELs, which, despite their smaller size, consistently yield hits and have superior physicochemical properties compared to 3-cycle DELs. The criteria for inclusion are where DEL provided a medicinal chemistry series, defined by off-DNA hit resynthesis, profiling in relevant assay(s), and follow-up SAR optimization.

Summary

This article provides an in-depth analysis of the design and application of DNA-encoded libraries (DELs) in medicinal chemistry. It examines recent case studies (2020−2025) where DELs have been successfully used to generate active series for drug discovery. Key learnings include the effectiveness of 2-cycle DELs in yielding hits with better physicochemical properties compared to 3-cycle DELs. The article also explores various DEL designs, including linear, branched, and heterocycle-formation designs, and highlights the importance of physicochemical properties in hit identification. The study concludes that while there is no clear correlation between DEL size and productivity, 2-cycle libraries have shown significant promise in generating high-quality hits.

Highlights

• DNA-encoded libraries (DELs) offer a powerful alternative to traditional high-throughput screening (HTS) for hit identification.
• Recent case studies (2020−2025) demonstrate the effectiveness of DELs in generating active series for medicinal chemistry.
• 2-cycle DELs, despite their smaller size, consistently yield hits with superior physicochemical properties compared to 3-cycle DELs.
• Key physicochemical properties, such as molecular weight (MW), topological polar surface area (TPSA), and hydrogen bond donors (HBD), are critical in library design.
• The article emphasizes the importance of well-established on-DNA chemistry and standard building block classes in generating diverse and high-quality DELs.

Conclusion

The analysis of recent DEL technology screens highlights the potential of 2-cycle DELs in generating high-quality hits with desirable physicochemical properties. While there is no clear correlation between library size and productivity, 2-cycle libraries have shown significant promise. The study underscores the importance of physicochemical properties in hit identification and the effectiveness of well-established on-DNA chemistry and standard building block classes in library design. Future DEL designs should continue to leverage these principles to accelerate drug discovery.