Atomistic insights into the inhibition of cysteine proteases: First QM/MM calculations clarifying the regiospecificity and the inhibition potency of epoxide- and aziridine-based inhibitors
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Milena Mladenovic
- Konstantin Junold
- Reinhold F Fink
- Walter Thiel
- Tanja Schirmeister
- Bernd Engels
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000255292300028&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/jp711287c
- eISSN
- 1520-5207
- Externe Identifier
- Clarivate Analytics Document Solution ID: 292UT
- PubMed Identifier: 18393547
- ISSN
- 1520-6106
- Ausgabe der Veröffentlichung
- 17
- Zeitschrift
- JOURNAL OF PHYSICAL CHEMISTRY B
- Paginierung
- 5458 - 5469
- Datum der Veröffentlichung
- 2008
- Status
- Published
- Titel
- Atomistic insights into the inhibition of cysteine proteases: First QM/MM calculations clarifying the regiospecificity and the inhibition potency of epoxide- and aziridine-based inhibitors
- Sub types
- Article
- Ausgabe der Zeitschrift
- 112
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Milena Mladenovic
- Konstantin Junold
- Reinhold F Fink
- Walter Thiel
- Tanja Schirmeister
- Bernd Engels
- DOI
- 10.1021/jp711287c
- eISSN
- 1520-5207
- ISSN
- 1520-6106
- Ausgabe der Veröffentlichung
- 17
- Zeitschrift
- The Journal of Physical Chemistry B
- Sprache
- en
- Online publication date
- 2008
- Paginierung
- 5458 - 5469
- Datum der Veröffentlichung
- 2008
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/jp711287c
- Datum der Datenerfassung
- 2023
- Titel
- Atomistic Insights into the Inhibition of Cysteine Proteases: First QM/MM Calculations Clarifying the Regiospecificity and the Inhibition Potency of Epoxide- and Aziridine-Based Inhibitors
- Ausgabe der Zeitschrift
- 112
Data source: Crossref
- Abstract
- Epoxides and aziridines are important building blocks for inhibitors of cysteine proteases which are promising drug targets for many diseases. In spite of the large amount of experimental data concerning inhibition potency, structure-activity relationships, and structural arrangements of enzyme-inhibitor complexes, little is known about the basic principles which connect the substitution pattern with the resulting activities. To shed some light on this issue which is essential for the rational design of improved compounds, we have studied the inhibition processes theoretically for various inhibitors using quantum mechanical/molecular mechanical hybrid approaches and classical molecular dynamics simulations. The careful analysis of the computational results allows insight into the interactions which govern the regio- and stereospecificity of the interactions. Known structure-activity relationships are rationalized in terms of the same interactions that determine the measured pH dependencies. Inconsistencies in existing X-ray structures are resolved through comparison with the computed structures, which leads to a reassessment of the factors that control the inhibition potency. Similarities and differences in the mode of action of epoxide- and aziridine-based inhibitors are elucidated. Finally the small reaction barriers computed for the irreversible step in E64 analogues call into question the commonly accepted two-step model of inhibition since the second, irreversible step is predicted to be so fast that suitably oriented enzyme-inhibitor complexes will react rather than dissociate and equilibrate.
- Addresses
- Institut für Organische Chemie, and Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany.
- Autoren
- Milena Mladenovic
- Konstantin Junold
- Reinhold F Fink
- Walter Thiel
- Tanja Schirmeister
- Bernd Engels
- DOI
- 10.1021/jp711287c
- eISSN
- 1520-5207
- Externe Identifier
- PubMed Identifier: 18393547
- Open access
- false
- ISSN
- 1520-6106
- Ausgabe der Veröffentlichung
- 17
- Zeitschrift
- The journal of physical chemistry. B
- Schlüsselwörter
- Epoxy Compounds
- Aziridines
- Cysteine Endopeptidases
- Cysteine Proteinase Inhibitors
- Binding Sites
- Binding, Competitive
- Molecular Structure
- Hydrogen Bonding
- Quantum Theory
- Models, Chemical
- Computer Simulation
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2008
- Paginierung
- 5458 - 5469
- Datum der Veröffentlichung
- 2008
- Status
- Published
- Datum der Datenerfassung
- 2008
- Titel
- Atomistic insights into the inhibition of cysteine proteases: first QM/MM calculations clarifying the regiospecificity and the inhibition potency of epoxide- and aziridine-based inhibitors.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 112
Data source: Europe PubMed Central
- Abstract
- Epoxides and aziridines are important building blocks for inhibitors of cysteine proteases which are promising drug targets for many diseases. In spite of the large amount of experimental data concerning inhibition potency, structure-activity relationships, and structural arrangements of enzyme-inhibitor complexes, little is known about the basic principles which connect the substitution pattern with the resulting activities. To shed some light on this issue which is essential for the rational design of improved compounds, we have studied the inhibition processes theoretically for various inhibitors using quantum mechanical/molecular mechanical hybrid approaches and classical molecular dynamics simulations. The careful analysis of the computational results allows insight into the interactions which govern the regio- and stereospecificity of the interactions. Known structure-activity relationships are rationalized in terms of the same interactions that determine the measured pH dependencies. Inconsistencies in existing X-ray structures are resolved through comparison with the computed structures, which leads to a reassessment of the factors that control the inhibition potency. Similarities and differences in the mode of action of epoxide- and aziridine-based inhibitors are elucidated. Finally the small reaction barriers computed for the irreversible step in E64 analogues call into question the commonly accepted two-step model of inhibition since the second, irreversible step is predicted to be so fast that suitably oriented enzyme-inhibitor complexes will react rather than dissociate and equilibrate.
- Autoren
- Milena Mladenovic
- Konstantin Junold
- Reinhold F Fink
- Walter Thiel
- Tanja Schirmeister
- Bernd Engels
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/18393547
- DOI
- 10.1021/jp711287c
- ISSN
- 1520-6106
- Ausgabe der Veröffentlichung
- 17
- Zeitschrift
- J Phys Chem B
- Schlüsselwörter
- Aziridines
- Binding Sites
- Binding, Competitive
- Computer Simulation
- Cysteine Endopeptidases
- Cysteine Proteinase Inhibitors
- Epoxy Compounds
- Hydrogen Bonding
- Models, Chemical
- Molecular Structure
- Quantum Theory
- Sprache
- eng
- Country
- United States
- Paginierung
- 5458 - 5469
- Datum der Veröffentlichung
- 2008
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2008
- Titel
- Atomistic insights into the inhibition of cysteine proteases: first QM/MM calculations clarifying the regiospecificity and the inhibition potency of epoxide- and aziridine-based inhibitors.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 112
Data source: PubMed
- Beziehungen:
- Property of