DNA-encoded libraries represent a novel approach for discovering small molecule ligands against protein targets of interest. In a DNA-encoded library, each unique DNA strand encodes information about a synthetic small molecule. Large libraries containing billions of different small molecules can be synthesized and tested in a massively parallel manner using sequencing technologies. This enables comprehensive and unbiased screening that surpasses the limitations of traditional high-throughput screening methods.
How DNA Encoded Libraries Work
In it, small molecules are synthesized as DNA-small molecule conjugates. Each conjugate contains a unique Global DNA Encoded Libraries tag that encodes information about the molecular structure. After synthesis, the library of conjugates is incubated with the protein target of interest. Any molecules that bind the target will be enriched, while non-binders are washed away. The DNA tags from enriched molecules can then be sequenced to discern the structures of hits. Selected molecules can be resynthesized based on their encoded information for further testing and optimization. hits. Selected molecules can be resynthesized based on their encoded information for further testing and optimization.
Global Effort To Develop Largest DEL
An international consortium of pharmaceutical companies and academic research labs have come together to create the world's largest DEL, containing trillions of unique small molecules. Called the Global DNA Encoded Library or GDEL, it aims to facilitate the discovery of valuable new drug leads. Large pharmaceutical companies involved in the project include GSK, Amgen, AstraZeneca, Sanofi and Boehringer Ingelheim. They have contributed significant financial and scientific resources to support library synthesis and screening at various academic centers.
Scale And Diversity Of GDEL
The scale of GDEL surpasses all previous DNA-encoded libraries. It contains over 100 billion synthetically feasible small molecules based on diverse scaffolds and building blocks contributed from all partners. This level of chemical diversity far exceeds what is possible through traditional library synthesis techniques alone. The library employs various linker chemistry designs to attach small molecules to DNA tags, maximizing binding interactions with target proteins. Its broad coverage of drug-like chemical space means it can reveal validated hits against any protein target of pharmacological relevance.
Global Screening And Data Sharing
Academic research groups involved in the GDEL initiative will independently screen the library against their protein targets of interest. These may include targets associated with cancer, neurological diseases, cardiovascular conditions, and other therapeutic areas. Using state-of-the-art sequencing and data analysis, they will discover high-quality small molecule ligands from the library. All screening data will be shared among partners to facilitate hit validation and chemical probe development on a global scale. The combined results are expected to reveal thousands of novel compounds with activity against various disease targets.
Applications In Target-Based Drug Discovery
The GDEL provides an unprecedented resource for target-based drug discovery programs. Academic labs can access its broad chemical diversity to identify initial scaffolds for new targets. Pharmaceutical partners can screen proprietary targets against the library to generate chemical matter for hit-to-lead campaigns. Confirmed hits would then undergo medicinal chemistry optimization by the respective organizations. Considering its scale and diversity, the GDEL is also well-suited for examining polypharmacology and discovering multitarget ligands. Its global, collaborative framework streamlines compound sharing between discovery partners. This helps advance new molecule candidates toward preclinical development more rapidly.
Future Prospects And Intellectual Property
As library synthesis and screening continues in the coming years, GDEL's scale and coverage of chemical space will expand significantly. Its partners envision increased contributions from additional pharmaceutical and biotech companies. Screening technologies will also improve to enable faster, larger-volume profiling. While initial screening data will be shared openly within the collaboration, intellectual property ownership of validated hits from proprietary targets remains with the respective organizations. Promising candidates may be protected via patent filings to support future clinical development. Over time, the DNA encoded libraries is poised to drive major new discoveries across multiple disease areas through collective, global drug hunting efforts.
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1. Source: Coherent Market Insights, Public sources, Desk research
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