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Approaching an experimental electron density model of the biologically active trans‐epoxysuccinyl amide group—Substituent effects vs. crystal packing |
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| Authors: | Ming W Shi Scott G Stewart Alexandre N Sobolev Birger Dittrich Tanja Schirmeister Peter Luger Malte Hesse Yu‐Sheng Chen Peter R Spackman Mark A Spackman Simon Grabowsky |
| Institution: | 1. School of Chemistry and Biochemistry, The University of Western Australia, Perth, WA, Australia;2. Anorganische Chemie und Strukturchemie, Heinrich‐Heine‐Universit?t Düsseldorf, Düsseldorf, Germany;3. Institut für Pharmazie und Biochemie, Johannes‐Gutenberg‐Universit?t Mainz, Mainz, Germany;4. Institut für Chemie und Biochemie, Anorganische Chemie, Freie Universit?t Berlin, Berlin, Germany;5. Fachbereich 2—Biologie/Chemie, Institut für Anorganische Chemie und Kristallographie, Universit?t Bremen, Bremen, Germany;6. ChemMatCARS, The University of Chicago, Argonne, IL, USA |
| Abstract: | The trans‐epoxysuccinyl amide group as a biologically active moiety in cysteine protease inhibitors such as loxistatin acid E64c has been used as a benchmark system for theoretical studies of environmental effects on the electron density of small active ingredients in relation to their biological activity. Here, the synthesis and the electronic properties of the smallest possible active site model compound are reported to close the gap between the unknown experimental electron density of trans‐epoxysuccinyl amides and the well‐known function of related drugs. Intramolecular substituent effects are separated from intermolecular crystal packing effects on the electron density, which allows us to predict the conditions under which an experimental electron density investigation on trans‐epoxysuccinyl amides will be possible. In this context, the special importance of the carboxylic acid function in the model compound for both crystal packing and biological activity is revealed through the novel tool of model energy analysis. |
| Keywords: | electron density epoxysuccinyl peptides invarioms model energies protease inhibitors |