Researchers at USC have created a groundbreaking method to automatically synthesize and test billions of different possible chemical compounds, a breakthrough with the potential to dramatically speed up the development of new drugs to treat medical issues.
Using DNA-Encoded Libraries
In the paper, the authors touch on DNA-encoded chemical libraries (DEL) as a way of enhancing discovery capabilities.
Conventional DEL technology has been restricted to about a million chemical compounds because the connecting of the DNA fragments with the chemical building blocks likely contained impurities and differences. That meant that as the ‘molecular soup’ competition was a race to test what worked, their title among individual active compounds in that quickly growing molecular soup was hard to pin down.
However, researchers from ETH Zurich have just created a game-changing approach to the problem. They have an incredible opportunity to wash that DEL all the way back down to only a single building block, because they can tie the synthesis of those molecules to magnetic particles. These vast DNA codes correctly represent the whole molecule, as opposed to a fragment, and would help enable much larger compound libraries (>several billion unique constructs).
Diversifying the Molecular Therapy Arsenals
The ETH Zurich team’s new DEL technology not only can handle much larger libraries of chemical compounds but also permits the synthesis of larger drug molecules — for example, ring-shaped peptides.
This is a major breakthrough because it may provide, for the first time in history, an alternative to identifying drug-like molecules that work on additional pharmacological targets other than — or in addition to — binding at small molecules’ canonical ‘lock-and-key’ fit. In addition, the larger molecules are not limited to the size of active centers and rather can be docked in specific parts on the protein surface, offering promise for more precise and less broad-based treatments.
Identifying small organic molecules that bind to specific protein surfaces is also of interest for basic biological research, as the discovery process permits the labeling and imaging of proteins in their cellular setting. On a broader scale, it can change the very nature of what we think are biological processes and how new therapeutics could be designed.
Conclusion
The DEL technology revolutionized by the ETH Zurich researchers provides an important rediscovery in drug discovery. By allowing researchers to synthesize and screen billions of unique chemical compounds, this technique could discover many more previously unidentified pharmacologically active molecules that will lead to better and affordable medical treatments. In addition, the extended palette creating larger, more complex molecules opens up additional opportunities to address proteins in novel manners leading to both medical therapies and basic biological research. We believe that this advance will help us demonstrate just how useful combinatorial chemistry can be in helping to shape the future of pharmaceutical and biomedical innovation.
