The importance of the active site histidine for the activity of epoxide- or aziridine-based inhibitors of cysteine proteases

Abstract

AbstractIn 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.

Autoren

Milena Mladenovic
Tanja Schirmeister
Stefan Thiel
Walter Thiel
Bernd Engels

DOI

10.1002/cmdc.200600159

eISSN

1860-7187

ISSN

1860-7179

Ausgabe der Veröffentlichung

1

Zeitschrift

ChemMedChem

Sprache

en

Online publication date

2006

Paginierung

120 - 128

Datum der Veröffentlichung

2007

Status

Published

Herausgeber

Wiley

Herausgeber URL

http://dx.doi.org/10.1002/cmdc.200600159

Datum der Datenerfassung

2023

Titel

The Importance of the Active Site Histidine for the Activity of Epoxide‐ or Aziridine‐Based Inhibitors of Cysteine Proteases

Ausgabe der Zeitschrift

2

Datenquelle: Crossref

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.

Addresses

Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany.

Autoren

Milena Mladenovic
Tanja Schirmeister
Stefan Thiel
Walter Thiel
Bernd Engels

DOI

10.1002/cmdc.200600159

eISSN

1860-7187

Externe Identifier

PubMed Identifier: 17066390

Open access

false

ISSN

1860-7179

Ausgabe der Veröffentlichung

1

Zeitschrift

ChemMedChem

Schlüsselwörter

Epoxy Compounds
Aziridines
Cysteine Endopeptidases
Histidine
Cysteine Proteinase Inhibitors
Binding Sites
Structure-Activity Relationship
Kinetics
Catalysis
Quantum Theory
Computer Simulation

Sprache

eng

Medium

Print

Paginierung

120 - 128

Datum der Veröffentlichung

2007

Status

Published

Datum der Datenerfassung

2006

Titel

The importance of the active site histidine for the activity of epoxide- or aziridine-based inhibitors of cysteine proteases.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

2

Datenquelle: Europe PubMed Central

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.

Autoren

Milena Mladenovic
Tanja Schirmeister
Stefan Thiel
Walter Thiel
Bernd Engels

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/17066390

DOI

10.1002/cmdc.200600159

eISSN

1860-7187

Ausgabe der Veröffentlichung

1

Zeitschrift

ChemMedChem

Schlüsselwörter

Aziridines
Binding Sites
Catalysis
Computer Simulation
Cysteine Endopeptidases
Cysteine Proteinase Inhibitors
Epoxy Compounds
Histidine
Kinetics
Quantum Theory
Structure-Activity Relationship

Sprache

eng

Country

Germany

Paginierung

120 - 128

Datum der Veröffentlichung

2007

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2008

Titel

The importance of the active site histidine for the activity of epoxide- or aziridine-based inhibitors of cysteine proteases.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

2

Datenquelle: PubMed

The importance of the active site histidine for the activity of epoxide- or aziridine-based inhibitors of cysteine proteases

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