A comparative study on the experimentally derived electron densities of three protease inhibitor model compounds.
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.
Freie Universität Berlin, Institut für Chemie und Biochemie/Kristallographie, Fabeckstr. 36a, 14195, Berlin, Germany.
Simon
S
Grabowsky
Thomas
T
Pfeuffer
Wolfgang
W
Morgenroth
Carsten
C
Paulmann
Tanja
T
Schirmeister
Peter
P
Luger
D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology; D001388:Aziridines / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004583:Electrons; D005027:Ethylene Oxide / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D009930:Organic Chemicals / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D055672:Static Electricity; D017356:Synchrotrons; D013696:Temperature
D000475:Alkenes; D001388:Aziridines; D009930:Organic Chemicals; D011480:Protease Inhibitors; D005027:Ethylene Oxide