DNA-Encoded Library (DEL) Screening

DNA-Encoded Library (DEL) screening is designed to maximize your chance for success while searching for unique binders to your biological targets in vast (>8 billion compounds) chemical space. Hit finding is focused on identifying molecules that bind to a protein target under different conditions, which can then be screened in functional, mechanism of action (MoA) assays.

We have partnered with X-Chem to provide our clients with access to world-leading DEL technology and expertise, aligned with our extensive drug discovery expertise. Our experienced team will work with you to understand your project criteria, curate a tailored collection, and perform the groundwork required, including protein production where required,to find relevant binders that are further characterized in their functional effect and MoA.

An appropriately designed DEL screening campaign can provide a clear MoA binding profile of your delivered hits:

  • Competition with a known binder provides binding site information
  • Addition of a substrate to induce conformational change provides cooperative binding information
  • Screening multiple targets or conditions in parallel achieves selectivity on closely related targets
  • When possible, we can synthesize an on-DNA control to validate selection data

DEL Screening Set Curation

DEL screening campaigns are run using X-Chem’s DELflex library of >8 billion compounds This collection is built with diversity, drug-like properties, and a focus on quality in mind.

Emphasis on diversifying the libraries and increasing the number of drug-like compounds ensures a continued focus on quality, in addition to library volume. DEL screens are vast by nature, but it’s important that the screening collection is high-quality as well as large, to provide the highest success rate. Campaigns are run with up to 6 different conditions to focus and align your DEL campaign with your research goals. High-quality libraries, DEL-focused protein production and quality control, and MoA-guided selection design are crucial for success when working in vast chemical space.

Our DEL team is experienced in conducting the in-depth data analysis required to ensure the optimal compounds for off-DNA synthesis are selected.

DEL Screening and Alternative Options

Charles River offers several options for exploring diverse chemical space with a binding screen approach, including DNA-Encoded Library screening.

AI-Enabled Drug Discovery (Logica)

We offer DNA-Encoded Library screening as part of our AI-driven drug discovery solution Logica™. Logica is a transformative solution advancing you from target to preclinical candidate, and enabling streamlined discovery lead time through integration and automation.

Logica enables you to search billions of molecules for the one optimal candidate you need to advance your program into the next phases of development. This approach has a 90% success rate in producing advanceable lead series, and utilizes a risk-sharing model with a strong cost:success relationship.

Affinity Selection Mass Spectrometry (Immobilized Array)

High-throughput affinity selection mass spectrometry (ASMS) can be used as a viable alternative to screening a DNA-encoded library.

Similarly to DEL screening, ASMS is a binding-based approach which offers diverse exploration of binding sites. ASMS can allow you to screen protein in a more natural state, and can circumvent potential binding interference from a DNA tag. ASMS operates within a much more compact chemical space than a DNA-encoded library. However, tactical curation of screening sets provides a broad scope of diversity, with confirmed hit data typically available within three to four weeks of screening initiation. In comparison, a DEL project would require resynthesis of the hit compounds to allow hit confirmation.

For a more extensive comparison of the two technologies, please see the FAQs below.

To explore DNA-Encoded Library screening via the Logica platform, or comparable binding screen alternatives such as ASMS, please reach out to our screening team.

Talk to our screening team

Frequently Asked Questions (FAQs) About DNA-Encoded Library (DEL) Screening

  • How do I know if DEL screening is the right Hit ID approach for my research?

    DEL screening can be a productive hit finding option across a range of research goals and circumstances, including:

    • Hit finding to support projects requiring linkers/binders, including bifunctional molecules such as degraders or compounds for tagging for assay development or proteomic studies
    • Hit finding against a high-value target where other hit identification methods are likely to be challenging
    • Hit finding in unique chemical space for commonly prosecuted targets
    • Requirement for rapid and/or end-to-end hit identification program with a focus on selectivity
    • Requirement to screen multiple conditions in parallel and delivery of clear MoA profiling of hits

    Our hit identification experts are experienced in evaluating your research requirements and recommending appropriate and optimized solutions. To discuss whether DEL screening could be the right approach for your Hit ID program, please get in touch with our team.

  • Is Affinity Selection Mass Spectrometry (ASMS) a good alternative to DEL screening?

    ASMS comes with multiple differences and similarities to DEL screening, so your research goals, target product profile, budget, timelines, and other parameters can all influence the comparability and advantages/disadvantages of these two screening methods in context with your own requirements.

    Below is a rough summary of some of the key differences, but for a more personalized and in-depth review of suitability, our experienced screening team are happy to have a no-pressure conversation with you to discuss your options.

    Timelines
    While a DEL can be rapid to initiate, end-to-end screening typically takes three to six months. ASMS screening is typically quicker, usually requiring three to four weeks once screening has been initiated. The Aspire Diversity compound collection is available in-house and pre-pooled to further expedite this process. Once hits have been identified with ASMS, they do not require resynthesis and are therefore able to be confirmed rapidly, resulting in a faster end-to-end time.

    Budget
    ASMS is typically more budget-friendly than DEL screening, as the number of compounds accessed and screened is much more compact and neither chromatography nor resynthesis are required.

    Chemical space and diversity
    Both approaches enable access to diverse chemical space. DEL screening via the Charles River Logica platform provides access to >11 billion compounds, whereas in-house compound selection for ASMS is available from a selection of ~1.4 million compounds.

    Our diversity collections are rigorously curated to cover broad chemical space, achieving comparable levels of diversity as the commercially available MolPort library, totaling ~7 million compounds. To find out more about the compound libraries available in-house at Charles River, download our free eGuide.

    Screening similarities
    Both DEL screening and ASMS are:

    • Binding-style screening approaches, enabling exploration of multiple compound binding sites
    • High-throughput
    • Well suited to prosecuting challenging or complex targets
    • Able to screen multiple conditions in parallel

    Screening differences

    • ASMS presents a more natural state for the target protein and circumvents any potential binding interference caused by the addition of a tag
    • DEL screening with a DNA-tag can potentially highlight compounds which are able to be functionalized easily with, for example, a linker to an E3 Ligase warhead
    • Hit validation and hit-to-lead can typically be accomplished faster following an ASMS screen, as the sequencing step is not required
  • Why is protein QC so important for DEL screening?

    Typically, DEL screening requires less protein than other hit identification methods, and in-house characterization and stringent protein quality control significantly increase its success rate. Off-the-shelf protein is typically not ideal for this type of study – as there tends to be a higher degree of aggregation, the percentage of active protein is usually quite low and the protein isn’t typically homologous. While this does not generally cause problems for biochemical assays, DEL screening requires a high degree of correctly folded protein to be effective; misfolded protein can pick up misleading background binders, reducing the quality of your program deliverables.

  • How long does DEL screening take?

    Once the protein is available, DEL screening typically takes between three and six months to execute. Protein production timelines vary depending on availability and quality of required proteins. Talk to our team to get an idea of your potential DEL timeline.