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What modern crystallography can add to pharmaceutical research?

Krzysztof Woźniak 1,2Maura D. Malińska 1,2Paulina M. Dominiak 1,2Andrzej Kutner 3

1. Uniwersytet Warszawski, Centrum Nowych Technologii (CENT), Żwirki i Wigury 93, Warszawa 02-089, Poland
2. University of Warsaw, Department of Chemistry, Pasteura 1, Warsaw, Warszawa 02-093, Poland
3. Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland


More than centuary ago, Max von Laue, William Henry Bragg and William Lawrence Bragg opened the field of structural applications of X-ray diffraction. Since then, the X-ray diffraction methods have been used to establish crystal and molecular structure of more than  milion compounds - among them many of pharmaceutical importance. However, modern crystallography can go far beyond routine crystal structure analysis.

In my contribution, I will discuss pros and cons of classical diffraction methods. Then will present the main ideas of modern methods based on quantitative studies of electron density in crystals. Such methods were introduced by Prof. Philip Coppens (SUNY, Buffalo, USA), who has started a new field of crystallographic and physicochemical research. Quantitave studies of electron density allow for far more detailed characterisation of properties of pharmaceutical substances in the solid state than any other classical X-ray diffraction techniques. My contribution will also cover quantitative relationships between atoms interactiong in crystals, and the role of factors influencing the quality of such relations such as: treatment of h-atoms, assumptions applied during refinement process and importance of neutron data both for charge densities and also for routine structural refinements. I will present relevant examples of such studies.

 I will also discuss the idea of pseudoatom databanks - now being intensively developed in our laboratory by my co-workers - containing the smallest transferable fragments of electron density, which can be used to reconstruct electron density in small molecules and proteins. This allows  to obtain energy of electrostatic interactions between drug molecules and proteins. In most pharmaceutical problems, these are electrostatic interactions which play the crucial role. Thus the methods based on reconstruction of electron density allow for optimisation of drug molecule properties  and design of better drugs. 




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Presentation: Invited oral at IX Multidyscyplinarna Konferencja Nauki o Leku, by Krzysztof Woźniak
See On-line Journal of IX Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2014-03-18 13:05
Revised:   2014-05-02 19:43