DNA Encoded Libraries (DELs) represent an advancement in the search for new medicines. This technology creates vast collections of small molecules, each marked with a specific DNA sequence. DELs efficiently identify molecules that interact with biological targets, such as disease-related proteins, accelerating early drug discovery.
Understanding DNA Encoded Libraries
A DNA Encoded Library is a collection of unique small molecules, each “tagged” with a distinct DNA sequence. This DNA tag serves as an identifier, allowing scientists to track each compound. The DNA itself is not the active drug compound; it functions solely as an informational label for the attached small molecule.
DELs contain immense diversity, comprising hundreds of millions to billions of distinct chemical structures, far exceeding traditional libraries. This vast diversity is achieved through combinatorial chemistry, linking different chemical building blocks to DNA tags. As new blocks are added, a corresponding DNA sequence is incorporated, recording the molecule’s history. The small molecules are typically organic compounds, synthesized directly onto or in close association with the DNA tags.
The DEL Screening Process
The DEL screening process begins by preparing the biological target, often a protein. The target is isolated and immobilized onto a solid support, like a magnetic bead, to facilitate later separation.
The entire DEL, containing billions of diverse small molecules, is then mixed and incubated with the immobilized target. Molecules with an affinity for the target protein will bind, allowing vast potential interactions simultaneously.
After incubation, washing steps remove unbound molecules, leaving only compounds attached to the immobilized target. This separation is important for enriching the sample with potential binding compounds.
Next, bound molecules and their DNA tags are eluted from the target, freeing potential binders for analysis. The DNA tags, serving as unique barcodes, are then amplified using Polymerase Chain Reaction (PCR), creating many detectable copies.
Finally, amplified DNA tags undergo high-throughput sequencing. This reads the unique DNA barcodes, identifying the sequence for each bound molecule. By comparing recovered DNA sequences to the original library, researchers link barcodes back to the specific chemical molecules that bound to the target, identifying “hits” with confirmed binding affinity.
Revolutionizing Drug Discovery
DNA Encoded Libraries are transforming drug discovery by offering several advantages over conventional methods. This technology accelerates identifying potential drug candidates, reducing time for early-stage discovery. Screening vast numbers of compounds simultaneously allows faster exploration of chemical space.
DELs also offer cost-effectiveness. They reduce material needed for screening and minimize individual compound purification and handling, streamlining workflow and lowering expenses.
A primary advantage of DELs is their capacity for vast diversity and scale. They enable simultaneous screening of hundreds of millions to billions of unique compounds, increasing the discovery of novel drug leads. This broad exploration can uncover compounds missed by traditional methods.
DELs are finding increasing application across various therapeutic areas. They identify potential drug candidates for complex diseases like cancer, infectious diseases, and neurological disorders by targeting specific proteins. The technology is also valuable for identifying binders to “undruggable” protein targets, which have been challenging to address. Ongoing evolution, including advancements in DNA-compatible chemistries and data analysis, suggests its importance in future pharmaceutical research.