Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases-Studies on Inhibition Mechanism and Kinetics.
作者： Philipp Klein , Fabian Barthels , Patrick Johe , Annika Wagner , Stefan Tenzer
DOI: 10.3390/MOLECULES25092064
关键词: Cysteine 、 Chemistry 、 Enzyme 、 1,4-Naphthoquinone 、 Protease 、 Proteases 、 Kinetics 、 Nucleophilic addition 、 Covalent bond 、 Stereochemistry
摘要: The facile synthesis and detailed investigation of a class highly potent protease inhibitors based on 1,4-naphthoquinones with dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position an electron-withdrawing group (EWG) 3-position is presented. One compound representatives, namely acid EWG = CN R H proved to be rhodesain inhibitor nanomolar affinity. respective benzyl ester (R Bn) was found hydrolyzed by target enzyme itself yielding free acid. Detailed kinetic mass spectrometry studies revealed reversible covalent binding mode. Theoretical calculations different density functionals (DFT) as well wavefunction-based approaches were performed elucidate mode action.
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