Drug discovery and development is a complex and tedious process requiring significant amount of time and resources. In fact, on average, the entire drug development process, from the demonstration of proof-of -concept to commercial launch, takes around 10-15 years and requires huge capital investments (USD 4-10 billion). Moreover, only a small fraction of early-stage therapeutic candidates are able to make it past preclinical testing, into clinical trials. Further, an even fewer number of clinical stage molecules are eventually approved for commercialization by the concerned regulatory authorities. The early stages of drug development, specifically the discovery of a specific molecular target and lead molecule, play an important role in the success of the drug in both preclinical and clinical studies. However, despite the advances in technology and improved understanding of biological systems, the drug discovery process is still considered to be lengthy, expensive, complex and inefficient. In fact, technological advancements in key disciplines, such as molecular biology and the emergence of new-generation biologics has made the process even more complicated.
Due to the aforementioned concerns, drug developers are gradually shifting their focus towards the use of novel discovery techniques, which include screening of combinatorial chemistry based large collections of compounds. Among all the screening techniques, DNA encoded library technology has captured the attention of drug developers, owing to its various advantages, including rapid and effective screening of large number of compounds, low investment and less requirement of storage space and streamlined drug discovery process. The DNA encoded library platform and services market is anticipated to grow at a CAGR of 16%, till 2035, according to Roots Analysis. Driven by the ongoing pace of innovation in this field and sufficient financial support from investors, the DNA encoded library market is likely to witness substantial growth during the forecast period.
OVERVIEW OF DNA ENCODED LIBRARIES
DNA encoded libraries have emerged as a robust and powerful tool, which combines the vast diversity of combinatorial chemistry and the versatile information encoding capabilities of DNA, to facilitate extremely high throughput molecular screening experiments. As indicated earlier, the use of DNA encoded libraries for hit generation is both cost effective and significantly expedites lengthy molecular screening processes. Fundamentally, the creation of a DNA encoded library is based on tagging small molecule / organic leads using short sequences of DNA and then using the combinatory chemistry approach to develop large numbers of structurally and functionally diverse molecules having unique DNA tags. Such a library can be synthesized within few weeks, typically containing millions to billions of compounds and using the following types of chemical reactions:
- Amide bond formation
- Nucleophilic aromatic substitutions
- Reductive amination
- Suzuki reactions
As mentioned earlier, screening experiments using such libraries are carried out in a single reaction tube for a singular biological target. In a typical screening experiment using a DEL, compounds that bind to the target are identified using their unique DNA tags and therefore easily isolated from the mixture. Such potential leads may be further incubated with the target, under varying conditions, in order to select the best candidate molecules, or hits. It is worth mentioning that the DNA tags on potential hits are designed to enable researchers to identify the reactions and molecular building blocks used for the synthesis of the same compounds.
KEY ADVANTAGES OF DNA ENCODED LIBRARIES
As highlighted earlier, the use of DNA encoded library technology is very helpful during the early stages of drug discovery since it requires less investment, time and storage space to identify target compounds. Apart from these, there are several other advantages as well associated with the application of DNA encoded libraries in drug development. The advantages offered by DNA encoded libraries includes:
Large Diversity: DELs can contain billions of unique compounds, making them a highly diverse source of potential drug candidates.
High Quality: Because each compound is linked to a unique DNA sequence, the quality of the library can be easily monitored and maintained.
Efficient Screening: DELs can be screened against a target protein in a single reaction, allowing for rapid identification of hits.
Cost-Effective: DELs can be synthesized in bulk, reducing the cost of library production.
Reduced False Positives: DELs are less prone to false positives than traditional libraries, as each compound is linked to a unique DNA barcode that allows for accurate identification.
Facilitates Hit-to-Lead Optimization: DELs can be used to identify hits that can be further optimized into lead compounds, making them a valuable tool in drug discovery
CHALLENGES AND LIMITATIONS ASSOCIATED WITH DNA ENCODED LIBRARIES
Despite having numerous advantages, DNA encoded libraries are fraught with various challenges including:
Library size: DELs can contain billions of compounds, but their size is still limited by the capacity of DNA synthesis and sequencing technologies. This means that some chemical space may not be covered by the library, limiting the diversity of compounds that can be discovered.
False positives: DELs can produce a large number of false positive hits due to non-specific binding of DNA tags to target proteins. This can lead to a significant amount of time and resources being spent on validating hits.
Binding kinetics: DELs can produce compounds that have high affinity for target proteins, but poor binding kinetics. This can result in compounds that are not effective in vivo and may not be suitable for drug development.
Cost: The cost of DNA synthesis and sequencing can be significant, especially when scaling up library production. This can limit the accessibility of DELs to smaller research groups.
Limited chemical diversity: DELs are limited to the chemical space that can be encoded by DNA, which may not cover all chemical space. This can limit the diversity of compounds that can be discovered.
FUTURE PERSPECTIVES AND OPPORTUNITY AREAS
Over time, a variety of DNA encoded library construction strategies have been developed and investigated by both academic and industry players. Further, the recent years have witnessed emergence of several stakeholders with increasing interest in DNA encoded libraries to support proprietary drug discovery programs. Additionally, with the aid of revolutionary artificial intelligence (AI) and machine learning (ML) tools, the process of DNA encoded libraries is being further streamlined using algorithms to navigate through these large datasets of compounds and predict the best drug targets. Although DNA encoded libraries have been successful in enabling the identification and isolation of hits against several types of target proteins, certain studies have reported their inability to be used to interrogate certain protein classes. Therefore, even though these libraries have gradually been accepted into mainstream drug discovery applications, there is still scope for further improvement. In this context, researchers engaged in this field are also anticipating advances in DNA sequencing technologies that will further increase the number of DNA tags that can be sequenced at a time. Experts believe that once the abovementioned challenges are addressed, it is likely to open up new opportunities for DNA encoded libraries. It is worth mentioning that the scientific community is actively petitioning for this technology to be made open source. It is, therefore, apt to assume that the future may witness greater interactions between public and private research groups and library developers / providers, focused on the discovery of pharmacological lead against a wide array of biological targets.
Roots Analysis is a global leader in the pharma / biotech market research. Having worked with over 750 clients worldwide, including Fortune 500 companies, start-ups, academia, venture capitalists and strategic investors for more than a decade, we offer a highly analytical / data-driven perspective to a network of over 450,000 senior industry stakeholders looking for credible market insights. All reports provided by us are structured in a way that enables the reader to develop a thorough perspective on the given subject. Apart from writing reports on identified areas, we provide bespoke research / consulting services dedicated to serve our clients in the best possible way.
