A DNA Encoded Chemical Library (DEL) is a scientific platform that merges chemistry and molecular biology to create vast collections of small molecules. This technology links each chemical compound to a unique DNA sequence, which serves as an identifiable tag. DELs are a powerful tool primarily used in the early stages of drug discovery, enabling researchers to explore a wide range of chemical structures.
The Core Concept of DNA Encoded Libraries
A DNA Encoded Chemical Library employs DNA as a unique “barcode” for each distinct chemical compound. This allows for the creation and tracking of enormous numbers of molecules simultaneously. The DNA fragment acts as an amplifiable genetic tag, making it possible to identify and quantify individual molecules within complex mixtures.
The principle of combinatorial chemistry is central to DELs. This approach involves combining different chemical building blocks in various arrangements to generate a diverse library of compounds. Each time a new building block is added to a growing molecule, a corresponding DNA sequence is also added, recording the chemical history of that specific compound. This method allows for the parallel synthesis of chemical structures and their corresponding DNA tags, enabling the creation of libraries with millions to billions of unique compounds.
Building and Screening Chemical Libraries
Building the Library
The construction of a DNA Encoded Chemical Library involves an iterative synthesis process, often utilizing a “split-and-pool” strategy. Initially, a set of unique DNA oligonucleotides, each with a coding sequence, is chemically linked to a corresponding set of small organic molecules. These oligonucleotide-conjugate compounds are then mixed and divided into multiple groups for further reactions.
In each subsequent step, a new set of chemical building blocks is coupled to the existing molecules, and an additional DNA oligonucleotide, encoding the newly introduced modification, is enzymatically attached to the DNA tag. This continuous process of chemical reaction followed by DNA encoding ensures that each final compound possesses a unique DNA sequence. This DNA tag records its entire synthetic pathway, allowing its chemical structure to be identified by sequencing its associated DNA.
Screening for Binders
Once the library is built, the screening process, known as affinity selection, identifies compounds that bind to a specific target protein. The DEL mixture is incubated with the target protein, which is immobilized on a solid support. Compounds that bind to the target remain attached, while unbound molecules are washed away through several stringent washing cycles.
The DNA tags of the compounds that successfully bind to the target are then amplified using Polymerase Chain Reaction (PCR). This amplification allows for the detection of low copy numbers of bound molecules. Subsequently, high-throughput DNA sequencing is performed to read the amplified DNA barcodes, which reveals the identity and relative quantity of the successful binding compounds. This process identifies potential drug candidates by linking their binding affinity to their chemical structure.
Applications in Drug Discovery
DNA Encoded Libraries have transformed early-stage drug discovery by accelerating the identification of novel chemical starting points. This technology is particularly useful for finding “hits” and “leads”—molecules that show initial binding to a disease-related target protein. DELs can screen billions of molecules in a single experiment, a process that would take decades with traditional methods.
DEL technology has been successfully applied to various pharmaceutical targets, including enzymes, receptors, and antibodies. It can identify compounds that modulate protein-protein interactions, such as inhibitors that block the activity of harmful proteins or compounds that bring two molecules together for a therapeutic effect. This approach allows for the exploration of broad chemical diversity, leading to the discovery of new chemical scaffolds.
Key Advantages of DNA Encoded Libraries
A primary advantage of DEL technology is its unparalleled scale and diversity. While traditional high-throughput screening (HTS) might screen up to one million compounds, DELs can explore libraries containing millions to billions, and even up to a trillion, unique molecules. This massive expansion of chemical space increases the likelihood of finding novel drug candidates.
DELs also offer considerable efficiency, reducing both the time and cost associated with early drug discovery. Screening vast numbers of compounds simultaneously in a single tube eliminates the need for individual well-plate testing. This results in a shorter time from screening to result analysis, often around 4 to 5 weeks. Furthermore, DELs require only a small amount of target protein. The technology also has the potential to discover entirely new chemical scaffolds that might not be found through other methods.