DNA-Encoded Library (DEL) Screening

Enhancing drug discovery with DEL screening 

High-throughput screening is a cornerstone of early-phase drug discovery, allowing the rapid identification of potential hit compounds. However, the costs associated with traditional chemical libraries can be as high as $1 billion USD, meaning this approach can quickly become expensive and resource intensive. 

DNA-encoded libraries (DELs) offer a powerful and cost-effective alternative to traditional high-throughput screening (HTS) methods. These consist of compounds linked to unique DNA barcodes, allowing for the simultaneous screening of vast compound libraries through affinity selection. In this process, compounds that bind to target molecules are enriched, and their DNA tags are sequenced for identification.  

This method allows millions of compounds to be tested in a single tube, vastly increasing the scale and efficiency of screening compared to traditional HTS, which typically involves individual compounds in 384 or 1536-well microplates. Furthermore, affinity selection workflows are highly amenable to automated liquid handling technologies to ensure their throughput, reliability and data quality. 

Understanding the DEL screening workflow 

A typical DEL screening workflow allows researchers to screen vast libraries of small molecules quickly and efficiently. 

• A diverse library of small molecules is synthesized through combinatorial chemistry, with each step including the addition of a DNA sequence that builds a unique barcode identifier. 

• The encoded libraries are incubated with the target protein. Non-binding ligands are removed through washing, ensuring that only specific binders remain. 

• Bound molecules are eluted, and their DNA is amplified. Sequencing then identifies the hits from the screening. 

The remaining steps then follow the typical drug discovery pathway. Hits are synthesized and validated independently to confirm their binding affinity and biological activity. The most promising candidates undergo optimization to enhance potency, selectivity, and pharmacokinetic properties, followed by preclinical and clinical testing. 

The role of automation in DEL screening 

Multiple steps the workflow involve manual pipetting steps and are therefore prime candidates for automated liquid handling: 

• Increased throughput: Automation enables the parallel synthesis of vast chemical libraries, significantly boosting throughput while reducing manual errors. 

• Streamlined screening: Automated systems can manage incubation, washing, and elution steps with precision, ensuring high-throughput and consistent data quality. 

• Enhanced NGS preparation: Automating PCR setup and DNA preparation for NGS sequencing allows for the accurate handling of small volumes, increasing speed and accuracy beyond what is possible manually. 

• Accelerated validation: Automation also speeds up downstream validation assays, making the overall process more efficient. 

For drug discovery labs, incorporating automation into DEL screening workflows means faster identification of promising candidates, more reliable results, and the ability to handle larger and more complex projects, ultimately accelerating the overall discovery process.