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Discovery & Development Drug Discovery

New Avenues

Docking is the most pragmatic approach to discover new small molecules to modulate protein function. The process enables scientists to model interactions between small molecules and proteins at the atomic level. Researchers at the University of California, San Francisco have used the docking technique for over two decades to discover new drug-like molecules. The process enables scientists to model interactions between small molecules and proteins at the atomic level and make predictions about the preferred orientation of molecules. The work of the researchers has resulted in the creation of ZINC, an enormous virtual pharmacology database, which will soon contain over a billion molecules. Could some of these be the blockbusters of the future? John Irwin a professor of pharmaceutical chemistry at UC San Francisco discusses the development of what they claim is the world’s largest pharmacology platform. 


What inspired the development of the platform?
In 2016, my colleagues and I learned about Enamine, a Kiev-based company that produces novel building blocks (including chemical reagents, scaffolds and intermediates) and screening libraries. By combining the various building blocks using over one hundred standard chemical reaction schemes, the company had a huge breakthrough in their ability to deliver hundreds of millions of never-before-made compounds on demand at the cost of around $100 per molecule. We were intrigued by their work and partnered with them with the hope of creating a new type of screening library.

With the support of the National Institutes of Health (NIH), we actively began to add the compounds produced by Enamine to our open-access platform, ZINC, and within the space of a few months our library had increased ten-fold in size and within the space of a year, 100-fold! ZINC now houses 750 million different compounds within its library. The hits generated from the platform can be downloaded in both 2D and 3D formats ready for docking. 

How does ZINC compare to other screening platforms?
ZINC is 100 times larger than the average high throughput screening library used in pharma. And although, in principle, DNA encoded libraries (DELs) are often reported to be of a similar size, we believe our library is much more chemically diverse because ours supports over 10 times as many bond-forming reactions to build it, and is more tolerant of diverse chemical functionality. Many medicinal chemistry programs lead to candidates that resemble the initial hit they began with. Our approach should open up entire new areas of chemical space for medicinal chemists to explore. 
 

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  1. JK Lyu et al. “Ultra-large library docking for discovering new chemotypes,” Nature. (2019). PMID: 30728502

About the Author

Maryam Mahdi

Assistant Editor

After finishing my degree, I envisioned a career in science communications. However, life took an unexpected turn and I ended up teaching abroad. Though the experience was amazing and I learned a great deal from it, I jumped at the opportunity to work for Texere. I'm excited to see where this new journey takes me!

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