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Diffracting electrons on nanocrystals enables faster and cheaper development of drugs

Scientists from the Institute of Physics of the Czech Academy of Sciences (FZU), University of Chemical Technology and Zentiva published an article on new ways of exploitation of electron diffraction on nanocrystalline materials [1]. The new method is faster and more accurate in determining the absolute configuration of organic molecules including those used in pharmaceuticals, and will significantly influence the process of development of new drugs: it will be cheaper and more effective.

“The determination of absolute configuration of newly synthesized molecules from nanocrystals has so far been extremely difficult though absolutely essential for the development of new pharmaceuticals. Regulatory bodies like U. S. Food and Drug Administration require this information before the drug is accepted for distribution. Our team has developed a new generally applicable method to determine the absolute configuration of molecules,” says Petr Brázda from the FZU, the main author of the article.

The new method will be used in laboratories and the development of drugs will become faster, simpler and more effective. “Pharmaceutical companies have already expressed interest in using our method,” says Lukáš Palatinus, the research group team leader.

The determination of absolute configuration of molecules is, for instance, essential with the chiral molecules, that is molecules with asymmetric spatial geometry. A chiral molecule is not identical with its mirror image in the same way as the left hand is not identical with the right hand – they are very similar, but they are not the same. All saccharides, proteins and DNA in live organisms, for instance, are composed from such molecules. If we exchanged a chiral molecule for its mirror image in a living organism, the mirror molecule would not function properly.

Two different absolute configurations of the molecule prolin (marked as L- a D-prolin) are a mirror image of each other (they are chiral). L-prolin can be found only in living organisms. With electron diffraction on nanocrystals the scientists were able to determine which of these molecules is contained in the drug during the preparation proces.

Most of modern pharmaceuticals are chiral molecules, and their mirror images usually have a different effect. While one molecule has the desired therapeutic effect, the effect of the other molecule may be much smaller, none or even harmful. This was also the well-known case of the drug Contergan, which in one of the forms helped against the morning sickness of pregnant women, while in the other it caused malformation of unborn babies.

The example of suitable and unsuitable forms of molecules shows how important is the knowledge of material crystal structure, and understanding of their properties. The field of structural crystallography that deals with the determination of atomic structure of crystalline matter is the main domain of the scientists from the Department of Structural Crystallography of the Institute of Physics, CAS. The application results of their new method on material containing the amino acid L-prolin and the molecule of antivirotic sofosbuvir were published on May 17, 2019 in the prestigious scientific journal Science [1]. The publication follows another publication of their work in the same journal two years ago, when it was selected to feature on the cover page [2]. The team lead by Lukáš Palatinus significantly advanced the method, which resulted in substantial improvement of the atom position determination in nanocrystals, crystals smaller than a hundredth of the diameter of human hair. In the current work, the authors extended the application of the method further to the fields where the knowledge of absolute configuration of molecules is indispensable, such as pharmaceutical research or molecular biology.

[1] Electron diffraction determines molecular absolute configuration in a pharmaceutical nanocrystal. P.Brázda, L. Palatinus and M. Babor, Science (2019).
[2] Hydrogen positions in single nanocrystals revealed by electron diffraction. L. Palatinus, P. Brázda, P. Boullay, O. Perez, M. Klementová, S. Petit, V. Eigner, M. Zaarour and S. Mintova, Science (2017).

About the FZU authors:

Mgr. Petr Brázda, Ph.D. graduated in organic chemistry at Faculty of Science, Charles University, Prague and he received his PhD at Faculty of Science, Charles University, Prague and Université L. Pasteur in Strasbourg. Next, he worked in the Institute of Inorganic Chemistry of the Czech Academy of Sciences. Since 2014, he is a member of the electron crystallography group lead by L. Palatinus at the Institute of Physics of the Czech Academy of Sciences. As a member of the team, he received the Award of the CAS for outstanding results of great scientific significance. He co-authored an article that won the „Outstanding Paper Award 2017 Instrumentation and Technique Development“ of the European Microscopy Society.

Petr Brázda

Dr. Lukáš Palatinus studied mineralogy and geochemistry at Faculty of Science, Charles University, Prague and he received his doctorate from University of Bayreuth. He worked in the group of prof. Gervais Chapuis at EPFL Lausanne. Since his return from Lausanne in 2009 he has worked at FZU in the department of Structural Analysis, where he has been the leader of the electron crystallography group. His research so far has been recognised by several prizes such as the Neuron Award and European Microscopy Society „Outstanding Paper Award 2017 Instrumentation and Technique Development”. He also lead the team that won the Award of CAS for outstanding results of great scientific significance.

Lukáš Palatinus