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Two well-known techniques + new application field = breakthrough of the year

The process of structure determination of small organic molecules made faster and more simply.
The process of structure determination of small organic molecules made faster and more simply.

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This fall, Dr. Tim Grüne from the Paul Scherrer Institute (PSI) together with Crystallise! AG published the results of their joint project, presenting to the scientific community a prototype device designed to find the structure of small molecules using nanocrystalline powders. By combining the electron source from a transmission electron microscope (TEM) and using a crystallographic approach, they succeeded in performing Electron Diffraction (ED). Scientific circles have been buzzing about the potential of this technique for the field of organic chemistry ever since. It was even nominated as a breakthrough of the year by Science magazine.

The precise structure determination of small organic molecules is crucial to drug discovery. Up until now, the go-to method for doing so has been X-ray diffraction. However, the whole process can be very long and unreliable because of one step – crystallization. Before the actual analysis, the molecules first need to be coaxed to a large crystal, which can be time-consuming and sometimes even impossible. Surprisingly, the solution to this challenge – electron diffraction – has been around for a long time: some inorganic chemists and material scientists have been using it since the mid-2000s. It is only that no one thought of applying it to organic chemistry the way Dr. Grüne and Crystallise! AG have done.

Solving the structure of small organic molecules

This fall, two papers were published almost simultaneously on the application of the electron diffraction technique to the identification of small organic molecules. One showed how the MicroED technique – usually only used for the structure identification of large molecules such as proteins – could be adapted to solve the structure of small molecules. The other, by Dr. Grüne from the Paul Scherrer Institute (PSI) in collaboration with Crystallise! AG, reports on the creation of a prototype device for finding the structure of small molecules, using the beam from an electron microscope and a compatible detector (EIGER X 1M, from Dectris AG).

A new electron diffractometer coming to the market

Grüne and Crystallise! managed to combine existing and familiar parts and techniques in a smooth system that enables chemists to perform the entire process of structure determination in a few hours, instead of weeks or even months. The prototyped device can process information from nanocrystals, thus making the crystal growth step of the process unnecessary. As a result, the application of this technique in organic chemistry could significantly speed up drug discovery. The potential impact of electron diffraction has been proven to be so high that the technique was among 10 nominations for a “Breakthrough of the Year” in Science Magazine.

Crystallise! AG is now planning to commercialize such a device. The company, in collaboration with partners, is already building its first electron diffractometer.