Abstract:
:In the present study the importance of the active site histidine residue (His) for the activity of epoxide- or aziridine-based cysteine protease inhibitors is examined theoretically. To account for all important effects, QM/MM hybrid approaches are employed which combine quantum mechanical (QM) methods that are necessary to describe bond-breaking and formation processes, with molecular mechanics (MM) methods that incorporate the influence of the protein environment. Using various model systems, the computations exclude a direct proton shift from the active site His residue to the inhibitor, but show that one water molecule is sufficient to establish a very efficient relay system. This relay system allows an easy proton transfer from the active site His residue to the inhibitor and is thus essential for the activity of both types of inhibitors. Differences between the epoxides and the aziridines are discussed, along with some implications for the rational design of optimized inhibitors. The work presented herein represents the first QM/MM study into the mode of action of these important inhibitor classes.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Mladenovic M,Schirmeister T,Thiel S,Thiel W,Engels Bdoi
10.1002/cmdc.200600159subject
Has Abstractpub_date
2007-01-01 00:00:00pages
120-8issue
1eissn
1860-7179issn
1860-7187journal_volume
2pub_type
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