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Automated DNA-Encoded Library Synthesis and Activity-Based Screening at the Attomole Scale
John P Burdick1, Erika M Cerna Arroyo1,2, Samantha R Levine1,2
1Department of Pharmaceutical Sciences, University of California, Irvine, California 92697, United States.
Journal of Medicinal Chemistry
|July 22, 2026
Summary
We developed a simplified DNA-encoded library (DEL) synthesis using magnetic beads and hydrogel encapsulation. This approach eliminates microfluidics for accessible drug discovery and screening.
Area of Science:
- Medicinal Chemistry
- Biotechnology
- Drug Discovery
Background:
- One-bead-one-compound DNA-encoded libraries (OBOC-DEL) offer vast chemical diversity for screening.
- Traditional OBOC-DEL methods require complex microfluidics and manual bead handling, limiting accessibility.
- There is a need for simplified, automatable OBOC-DEL platforms for broader use.
Purpose of the Study:
- To develop an ultraminiaturized, automatable OBOC-DEL platform.
- To enable in-gel activity-based assays without microfluidics.
- To enhance the accessibility and distributability of DEL technology.
Main Methods:
- Utilized 2.8-μm magnetic beads for DEL synthesis.
- Encapsulated beads in functionalized polyacrylamide hydrogels for in-gel assays.
- Developed automated solid-phase synthesis using a KingFisher instrument and bulk emulsification.
Main Results:
- Achieved high magnetic bead loading capacity (∼10 amol small molecule, ∼10^4 DNA tags per bead).
- Successfully performed activity-based screening against Factor Xa without microfluidics.
- Identified enzyme inhibitors, including the positive control rivaroxaban, as the most abundant hit.
Conclusions:
- The developed platform simplifies OBOC-DEL synthesis and screening.
- Magnetic beads and hydrogel encapsulation overcome limitations of traditional methods.
- This accessible technology broadens the application of DNA-encoded libraries in drug discovery.
