6533b82efe1ef96bd1292694
RESEARCH PRODUCT
Approaching an experimental electron density model of the biologically active trans ‐epoxysuccinyl amide group—Substituent effects vs. crystal packing
Peter LugerPeter R. SpackmanSimon GrabowskySimon GrabowskyBirger DittrichMark A. SpackmanTanja SchirmeisterMing W. ShiScott G. StewartYu-sheng ChenMalte HesseAlexandre N. Sobolevsubject
chemistry.chemical_classificationElectron densitybiology010405 organic chemistryChemistryCarboxylic acidOrganic ChemistryIntermolecular forceSubstituentActive siteContext (language use)010402 general chemistry01 natural sciences0104 chemical sciencesCrystallographychemistry.chemical_compoundAmideIntramolecular forcebiology.proteinPhysical and Theoretical Chemistrydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-01-24 | Journal of Physical Organic Chemistry |