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

Grabowsky, Simon; Pfeuffer, Thomas; Morgenroth, Wolfgang; Paulmann, Carsten; Schirmeister, Tanja; Luger, Peter (2008). A comparative study on the experimentally derived electron densities of three protease inhibitor model compounds. Organic & biomolecular chemistry, 6(13), pp. 2295-2307. Royal Society of Chemistry 10.1039/b802831a

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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 , oxirane and acceptor-substituted olefin ) 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 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 (conventional X-ray source vs. synchrotron radiation) gave an estimate concerning the reproducibility of the quantitative results.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Grabowsky, Simon

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

1477-0520

Publisher:

Royal Society of Chemistry

Language:

English

Submitter:

Simon Grabowsky

Date Deposited:

05 Feb 2020 16:31

Last Modified:

05 Feb 2020 16:31

Publisher DOI:

10.1039/b802831a

BORIS DOI:

10.7892/boris.138501

URI:

https://boris.unibe.ch/id/eprint/138501

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