by DNA encoded libraries (DELs) are a relatively new technique in drug discovery that employs the encoding of small molecule structures into DNA sequences. This allows for the screening of billions of drug-like compounds in a single experiment through the use of DNA-encoded small molecules. By assigning a unique DNA sequence to represent each small molecule structure, large chemical libraries can be rapidly screened for biological activity. This has significant potential to accelerate hit identification in drug discovery projects.
Encoding Small Molecules Into DNA
The process of creating a DEL begins by designing and synthesizing a collection of small molecule structures that contain diversity at functional groups known to be important for interactions with protein targets. These small molecules are first synthesized as organic compounds and then each molecule is coupled to a unique DNA barcode.
The Global DNA Encoded Libraries acts as a molecular tag to label and identify the small molecule. All the different small molecule-DNA conjugates are then pooled together to create the DEL library, with each member of the library represented by a unique DNA sequence. This enables the library to be screened as an entirely DNA-encoded collection.
High-Throughput Screening Using DNA Encoded Libraries
DEL libraries allow for ultra-high throughput screening approaches not possible with traditional small molecule libraries. The encoded DNA pool can be rapidly screened through affinity selection methods to isolate DNA sequences that encode hits against a target of interest. This involves incubating the entire DEL library with the target protein immobilized on a solid support. Any DNA-tagged small molecules that interact with or bind the target protein will be captured on the solid support along with their encoding DNA sequence. The non-binding members of the library can then be washed away.
The DNA encoding the hits are then amplified through polymerase chain reaction (PCR) and sequenced to reveal the structure of the active small molecules. Since each molecule has a unique DNA barcode, a single experiment can potentially screen billions of compounds and directly identify hits all through the decoding of their DNA sequences. No individual compound handling or purification is required. This massively parallel screening capability enables much faster hit identification compared to traditional high-throughput screening (HTS) with separate small molecules.
Applications And Advantages Of DEL Technology
DNA encoded libraries have several advantages over conventional small molecule libraries that have made them an attractive tool for drug discovery applications:
– Higherscreening capacity – As a single pooled library, DNA encoded libraries can potentially screen upwards of billions of compounds in a single experiment. This vastly exceeds the capacities of traditional plate-based HTS.
– No compound purification – Hits are directly identified by sequencing their encoding DNA rather than purifying individual molecules. This simplifies hit validation assays.
– Application to target classes – DELs have been used to screen proteins, nucleic acids, carbohydrates, and even whole cells/organisms which widens their utility compared to plate-based methods.
– Generates structural insight – The DNA sequencing data provides information on the chemical structure of hits which gives insight into preferred chemotypes and structure-activity relationships.
– Collection of ultralarge focused libraries – It is possible to design and synthesize DEL libraries highly enriched in drug-like chemotypes focused on a particular target class.
– Compatible with various assay formats – DNA encoded libraries screening can be adapted to different biophysical and biochemical assay technologies like mass spectrometry, fluorescence polarization, ELISA etc. beyond traditional binding assays.
Expanding Applications And Future Outlook
Since their introduction around 2010, DEL methodology and library designs have advanced significantly. Commercially available DELs now contain hundreds of millions to billions of compounds within focused drug-like spaces. The technique has found applications in identifying inhibitors against various targets like protein-protein interactions, protein degradation tags, antibacterial compounds, epigenetic targets and more. DEL screening has already yielded several preclinical drug candidates and is expected to contribute substantially to academic and pharmaceutical drug discovery pipelines.
With improving DNA sequencing technologies, future DEL libraries may encode up to trillions of diverse structures within feasible costs. This will enable exploring ever more complex structure-activity relationships at an unprecedented scale. DELs may also find additional applications beyond small molecule discovery like encoding and screening biomolecules, chemical probes and molecular probes. Overall, DNA encoded libraries screening technology holds great promise to augment traditional methods and catalyze the drug discovery process in the coming years.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
About Author - Ravina Pandya
Ravina Pandya,a content writer, has a strong foothold in the market research industry. She specializes in writing well-researched articles from different industries, including food and beverages, information and technology, healthcare, chemicals and materials, etc. With an MBA in E-commerce, she has expertise in SEO-optimized content that resonates with industry professionals. LinkedIn Profile
