Imagine a scenario where you could assess the binding of billions of molecules to your target within hours and without specialized equipment. Such a capability would unlock unprecedented possibilities in the life sciences. This is precisely what makes DNA-encoded libraries (DELs) so revolutionary. DELs empower scientists to sample chemical libraries of unmatched size and diversity using a streamlined affinity selection protocol. It is no surprise that within just a few years, DELs have advanced from an obscure technology to a cornerstone in pharmaceutical hit discovery. Countless success stories from diverse teams underscore the profound impact of DELs in uncovering novel chemical entities. However, what we have witnessed thus far may only be the beginning of even more transformative breakthroughs. By integrating them with cutting-edge technologies such as machine learning and structure-based drug discovery, conducting selections in living systems, and expanding their reach to new target classes, DELs promises to reshape the life sciences landscape. Staying ahead in DEL innovation will be imperative for any bioscience unit aspiring to be at the forefront of pharmaceutical advancements.

The power of DELs originates from ingeniously connecting chemical structures of library molecules to easily readable DNA sequences. By leveraging modern DNA amplification and sequencing technologies, linking molecules to DNA barcodes allows for the seamless conversion of chemical structure into data suitable for computer processing. DNA-encoding enables the identification of target binders through a simple affinity selection protocol. During selection, just a few microliters of a DEL are incubated with an immobilized target, followed by wash steps to remove low-affinity binders. The retained molecules are then easily identified through PCR amplification and DNA sequencing. Remarkably, this entire process takes only a few hours, without the need for target-specific bioassays and using readily available equipment. By sequencing the DNA barcodes, enriched molecules are indicated as potential target ligands. This streamlined workflow not only expedites drug discovery and cuts costs but also has the potential to democratize medicinal chemistry. By granting access to hit discovery methodology to scientists without advanced high-throughput screening infrastructure and enabling exploration of investigational drug targets, DELs pave the way for a more inclusive and innovative future in drug discovery.

Even users with a good understanding of DEL fundamentals often encounter challenges due to the opaque nature of DELs. Users typically have limited insights into the structures, building blocks, and synthetic protocols used to prepare DELs, which are crucial for reliable results. Problems during selection protocols and statistical effects can also impact the reliability of DEL data, making hit triaging challenging. Therefore, a solid understanding of DEL principles is essential to avoid delays and prioritize genuine hits. Our mission is to assist scientists in successfully navigating this technology. We offer guidance, critically evaluate DEL resources and processes, and provide expert reviews of research plans. Sometimes, an external perspective is all that's needed to prevent costly failures.

Currently, DELs are primarily used for the discovery of small-molecule binders to protein targets. However, this is just the tip of the iceberg in terms of the potential applications of DELs. Exciting new areas of research are emerging, such as the integration of DELs with machine learning (ML) methodologies. ML has the potential to revolutionize drug development, but obtaining large and useful datasets is a challenge. DELs can address this by providing datasets that map out the interactions between small molecules and their targets. However, it is crucial to understand the intricacies and limitations of DEL data to effectively implement ML approaches. In addition to supervised ML, alignment-based methods and combinations with structure-based approaches show great promise for drug development. Furthermore, there is growing interest in novel screening protocols, including photo-affinity approaches, DELs for covalent inhibitor discovery, and selections under physiologically relevant conditions. DELs specific to discovering molecular degraders and RNA-targeting molecules are also of high importance. Our consulting services can provide an updated evaluation of the current state of the art and help identify future opportunities as they arise.