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Issue 13, 2008
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A comparative study on the experimentally derived electron densities of three protease inhibitor model compounds

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Abstract

In order to contribute to a rational design of optimised protease inhibitors which can covalently block the nucleophilic amino acids of the proteases' active sites, we have chosen three model compounds (aziridine l, oxirane 2 and acceptor-substituted olefin 3) for the examination of their electron-density distribution. Therefore, high-resolution low temperature (9, 27 and 100 K) X-ray diffraction experiments on single-crystals were carried out with synchrotron and conventional X-radiation. It could be shown by the analysis of the electron density using mainly Bader's Theory of Atoms in Molecules, Volkov's EPMM method for interaction energies, electrostatic potentials and Gatti's Source Function that aziridine l is most suitable for drug design in this field. A regioselective nucleophilic attack at carbon atom C1 could be predicted and even hints about the reaction's stereoselectivity could be obtained. Moreover, the comparison between two data sets of aziridine l (conventional X-ray source vs. synchrotron radiation) gave an estimate concerning the reproducibility of the quantitative results.

Graphical abstract: A comparative study on the experimentally derived electron densities of three protease inhibitor model compounds

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Publication details

The article was received on 19 Feb 2008, accepted on 28 Mar 2008 and first published on 02 May 2008


Article type: Paper
DOI: 10.1039/B802831A
Org. Biomol. Chem., 2008,6, 2295-2307

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    A comparative study on the experimentally derived electron densities of three protease inhibitor model compounds

    S. Grabowsky, T. Pfeuffer, W. Morgenroth, C. Paulmann, T. Schirmeister and P. Luger, Org. Biomol. Chem., 2008, 6, 2295
    DOI: 10.1039/B802831A

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