Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases-Studies on Inhibition Mechanism and Kinetics.
Molecules
; 25(9)2020 Apr 28.
Article
in En
| MEDLINE
| ID: mdl-32354191
ABSTRACT
The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Trypanocidal Agents
/
Cysteine Proteinase Inhibitors
/
Naphthoquinones
/
Cysteine Proteases
Language:
En
Journal:
Molecules
Journal subject:
BIOLOGIA
Year:
2020
Document type:
Article
Affiliation country:
Germany