DNA-Encoded Library Technology (ELT)

DNA encoded library (DEL) is a new screening platform commonly used to discover small-molecules that interfere with the activity of pharmaceutically relevant proteins. DNA-encoded chemical libraries are hybrid-type collections of combinatorial organic molecules, individually coupled to distinctive DNA fragments.

The discovery of a novel drug is usually a multi-phase process, and one of central steps in drug discovery is the identification of binding molecules to protein targets of pharmaceutical interest. Some methods including high-throughput screening (HTS), fragment-based drug discovery, and computer-assisted drug discovery are available for early drug hit discovery. The molecular diversity and quality of the screening collection can be crucial in using HTS to discover compounds having desirable pharmacological properties . Whereas, the costs of assembling, maintaining and screening a library collection using HTS sets a practical upper limit on the number of compounds, and therefore the molecular diversity, that can be screened. By contrast, biological selection methods has largely relied on the expression and screening of peptides and proteins that are encoded by DNA and expressed by a cell, so biology-based drug discovery facilitate the construction and screening of libraries containing billions of polypeptides.

The Encoded Library Technology (ELT) platform integrates synthesis of DNA-encoded libraries (Figure 1), affinity selection against a target of interest, DNA sequencing, data translation, off-DNA compound synthesis and evaluation of off- DNA compounds for activity into a multicomponent process for ligand discovery.

Synthesis of DNA-Encoded Library

Typically, a DNA-encoded chemical library (DECL) is incubated with an immobilized protein of interest; subsequently, wash steps remove weak binders whereas molecules with high target affinity are retained on the solid support (Figure 2). Bound DNA-tagged molecules can then be eluted by heat-denaturation of the target protein and high-throughput DNA sequencing deconvolutes the structures of high affinity target binders.

Scheme for the selection of DNA-encoded chemical library (DEL) against biological targets

Reference:

Svetlana Belyanskaya, Yun Ding, James Callahan, Aili Lazaar, and David Israe. (2017). Discovering Drugs with DNA-Encoded Library Technology: From Concept to Clinic with an Inhibitor of Soluble Epoxide Hydrolase. Chembiochem, 18(9), 837-842.

Bingbing Shia, Yu Zhoua, Yiran Huang, Jianfu Zhang and Xiaoyu Li. (2016). Recent Advances on the Encoding and Selection Methods of DNA-encoded Chemical Library. Bioorg Med Chem Lett, 27(3), 361-369.

Lik Hang Yuen and Raphael Franzini. (2016). Achievements, Challenges, and Opportunities in DNA-Encoded Library Research: An Academic Point of View. Chembiochem, 18(9), 829-836.

Robert A. Goodnow Jr, Christoph E. Dumelin, Anthony D. Keefe. (2017). DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nature Reviews Drug Discovery, 16, 131–147.