DELability – Protein Assessment for DEL Screening

Over the last 5 years, biopharma has fully embraced the use of DNA-encoded libraries (DELs) for hit identification for all kinds of targets. The reasons are obvious: DEL screening tests billions of molecules in a single experiment to identify modulators of the target from this vast assortment of compounds. DEL screening is powerful and proven — at X-Chem, we have identified hundreds of hit families across a wide variety of targets for our partners and clients. Many companies now include DEL screening in their arsenal for routine hit identification. Nevertheless, many of our clients ask whether their target is suitable for DEL.

Let’s explore what’s behind this question:

DEL screening is affinity based. The target protein typically contains an immobilization handle (e.g., a His-tag, biotin), and target binders are “fished out” of the ocean of compounds simply through immobilization of the protein and washing away the unbound compounds. Success in this process depends on many factors: reliable encoding of each compound in the DEL, reproducible amplification of the bound fraction, quality informatics, filtering for promiscuous hits, etc. Our clients take most of these aspects of DEL screening for granted — they can do so because our experts have spent many years developing reliable, robust protocols for making and screening DELs.

The biggest variable, of course, is the target protein itself. DEL screening thrives on high-quality protein. But what does “high-quality” really mean here? When is a protein reagent good enough? The list of questions relevant to this issue is long: What’s the right construct? What’s the right tag, and where should I put it? What purity is sufficient? Is aggregation a problem? What kind of buffer should I use? What if my target consists of more than one subunit? Who could help us make the protein? These are just a few typical target-related questions among the many we encounter.

Our team can help by providing answers to specific questions, generally guiding clients on decisions while offering input along the way or even taking on the protein generation (through our trusted partners). If there is protein in hand, we now also offer a new tool: DELability, a fast and inexpensive screening-based feasibility assessment of protein reagents for their suitability for a DEL screen.

How does a DELability assessment work?

For each DELability assessment, our team will use as little as 100 µg of your target and screen it against X-Chem’s DELflex library deck, which encompasses more than 7.5 billion DNA-encoded compounds. The screen output will be subjected to rigorous computational filtering to eliminate matrix binders and non-specific “hits,” and will then be automatically clustered by chemical similarity. We will report the number of prospective high-quality target engagers in our DELflex library deck, as well as their structural clustering patterns. In addition, our team will assess your target’s output based on our 10+ years of DEL expertise and provide recommendations for proceeding into a full-fledged DEL screening campaign.

What is the advantage of DELability?

DELability is a fast way to de-risk the decision to conduct a full DEL screen. Within 30 days of reagents arriving at X-Chem, we will provide a response regarding the suitability of each target reagent for DEL screening. The client can test a single target with multiple constructs or explore dozens of target reagents or buffer conditions in parallel. X-Chem scientists can advise on the best screening conditions for the target, or the client can keep the target identity completely anonymous.

So whether you have an expansive portfolio of targets and need to decide which ones to prioritize for DEL screening, or you are working on a specific target and looking for the best constructs and screening conditions to obtain optimal DEL output, or maybe you are wondering whether DEL screening is the right approach for your very novel target, the DELability offering is an ideal entry point into X-Chem’s DEL-driven drug discovery process.

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