DEL: A New Drug Discovery Strategy for Membrane Protein

Pools of DNA-tagged tiny molecules called DNA-encoded libraries (DELs) make it simple to screen for and identify biomacromolecule binders. Due to the DELs' successful development, screening hits have entered clinical trials and have taken on a more significant role in medication research. DELs are collections of small-molecule combinations that are each connected to a specific DNA sequence, allowing for their clear identification. These small-molecule libraries can now be employed with straightforward affinity selection techniques that were modeled after phage display and related technologies thanks to DNA encoding. Although this mini-review solely focuses on small molecule DELs, DNA-encoded libraries cover a wide range of discovery approaches, including phage display, mRNA display, and SELEX. The immobilized protein of interest is typically incubated with a DEL, after which wash procedures remove weak binders while keeping molecules with high target affinity on the solid support. The structures of high-affinity target binders are clarified by amplifying the DNA-tags of surface-retained small molecule conjugates and high-throughput DNA sequencing. This quick and affordable screening approach works with extremely big libraries and just calls for common lab supplies. This method is quicker and easier than the often used HTS, which uses appropriate bioassays to individually test each candidate drug in a separate well.

DNA-encoded libraries (DELs). Fig.1 DNA-encoded libraries (DELs). (Yuen & Franzini, 2017)

Encoding Strategies

It might be useful to distinguish between "single-pharmacophore libraries" and "dual-pharmacophore libraries" while thinking about DEL encoding methods. Individual chemical moieties are connected to separate DNA segments in single-pharmaco-phore libraries (either in single-stranded or double-stranded format). In dual-pharmacophore libraries, two various chemical moieties are joined to the ends of complementary DNA strands, working in concert to recognize particular proteins. Furthermore, it is useful to distinguish between synthetic processes in which the identities of individual molecules' building blocks are encoded through the repetitive ligation of tiny DNA fragments and pre-defined DNA sequences that direct library development.

Schematic representation detailing the encoding strategies for DNA-templated synthesis of chemical libraries. Fig.2 Schematic representation detailing the encoding strategies for DNA-templated synthesis of chemical libraries. (Gironda-Martínez, 2021)

Encoded Libraries in Academic Drug Discovery

In comparison to traditional HTS libraries, DECLs are less expensive to create; in addition, DECL screening is quick, affordable, and only needs conventional laboratory infrastructure. DECLs eliminates the need for complex robotics and laborious assay development for screening. The fact that costs for library preparation are incurred upfront and only amortize over a lengthy period of time adds another difficulty to DECLs. Prior to library synthesis, large sets of oligonucleotides and building blocks must be collected. Before library preparation, laborious reactivity tests and optimization studies may also be required. The distribution of reaction yields for various sets of building blocks has been documented by a number of researchers, but the reactivity of the actual structures is typically unknown and must be determined again by each team. Further requirements for DECL research include software for sequencing analysis, high-quality target proteins, and the development and validation of screening methods.

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  1. Yuen, L.H.; Franzini, R.M. Achievements, Challenges, and Opportunities in DNA‐Encoded Library Research: An Academic Point of View. ChemBioChem. 2017, 18(9): 829-836.
  2. Gironda-Martínez, A.; et al. DNA-Encoded chemical libraries: a comprehensive review with successful stories and future challenges. ACS Pharmacology & Translational Science. 2021, 4(4): 1265-1279.
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