Predicting 19F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase-Inhibitor Complex

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Johannes CB Dietschreit
  • Annika Wagner
  • T Anh Le
  • Philipp Klein
  • Hermann Schindelin
  • Till Opatz
  • Bernd Engels
  • Ute A Hellmich
  • Christian Ochsenfeld
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000535042400001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1002/anie.202000539
eISSN
1521-3773
Externe Identifier
  • Clarivate Analytics Document Solution ID: NF1FD
  • PubMed Identifier: 32239740
ISSN
1433-7851
Ausgabe der Veröffentlichung
31
Zeitschrift
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Schlüsselwörter
  • African sleeping sickness
  • covalent inhibitors
  • NMR spectroscopy
  • quantum chemistry
  • structural biology
Paginierung
12669 - 12673
Datum der Veröffentlichung
2020
Status
Published
Titel
Predicting <SUP>19</SUP>F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase-Inhibitor Complex
Sub types
  • Article
Ausgabe der Zeitschrift
59

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Abstract
<jats:title>Abstract</jats:title><jats:p>The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor–protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable <jats:sup>19</jats:sup>F chemical‐shift predictions to deduce ligand‐binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the <jats:sup>19</jats:sup>F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleeping sickness. We include many protein–inhibitor conformations as well as monomeric and dimeric inhibitor–protein complexes, thus rendering it the largest computational study on chemical shifts of <jats:sup>19</jats:sup>F nuclei in a biological context to date. Our predicted shifts agree well with those obtained experimentally and pave the way for future work in this area.</jats:p>
Autoren
  • Johannes CB Dietschreit
  • Annika Wagner
  • T Anh Le
  • Philipp Klein
  • Hermann Schindelin
  • Till Opatz
  • Bernd Engels
  • Ute A Hellmich
  • Christian Ochsenfeld
DOI
10.1002/anie.202000539
eISSN
1521-3773
ISSN
1433-7851
Ausgabe der Veröffentlichung
31
Zeitschrift
Angewandte Chemie International Edition
Sprache
en
Online publication date
2020
Paginierung
12669 - 12673
Datum der Veröffentlichung
2020
Status
Published
Herausgeber
Wiley
Herausgeber URL
http://dx.doi.org/10.1002/anie.202000539
Datum der Datenerfassung
2023
Titel
Predicting <sup>19</sup>F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex
Ausgabe der Zeitschrift
59

Datenquelle: Crossref

Abstract
The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor-protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable <sup>19</sup> F chemical-shift predictions to deduce ligand-binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the <sup>19</sup> F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleeping sickness. We include many protein-inhibitor conformations as well as monomeric and dimeric inhibitor-protein complexes, thus rendering it the largest computational study on chemical shifts of <sup>19</sup> F nuclei in a biological context to date. Our predicted shifts agree well with those obtained experimentally and pave the way for future work in this area.
Addresses
  • Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, 81377, Munich, Germany.
Autoren
  • Johannes CB Dietschreit
  • Annika Wagner
  • T Anh Le
  • Philipp Klein
  • Hermann Schindelin
  • Till Opatz
  • Bernd Engels
  • Ute A Hellmich
  • Christian Ochsenfeld
DOI
10.1002/anie.202000539
eISSN
1521-3773
Externe Identifier
  • PubMed Identifier: 32239740
  • PubMed Central ID: PMC7496126
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft: SFB 1309 - 325871075
Open access
true
ISSN
1433-7851
Ausgabe der Veröffentlichung
31
Zeitschrift
Angewandte Chemie (International ed. in English)
Schlüsselwörter
  • Trypanosoma brucei brucei
  • Fluorine
  • Pyrimidinones
  • Thiophenes
  • Protozoan Proteins
  • Enzyme Inhibitors
  • Trypanocidal Agents
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Mutation
  • Thioredoxins
Sprache
eng
Medium
Print-Electronic
Online publication date
2020
Open access status
Open Access
Paginierung
12669 - 12673
Datum der Veröffentlichung
2020
Status
Published
Publisher licence
CC BY-NC-ND
Datum der Datenerfassung
2020
Titel
Predicting <sup>19</sup> F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase-Inhibitor Complex.
Sub types
  • brief-report
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
59

Files

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/anie.202000539 https://europepmc.org/articles/PMC7496126?pdf=render

Datenquelle: Europe PubMed Central

Abstract
The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor-protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable 19 F chemical-shift predictions to deduce ligand-binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the 19 F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleeping sickness. We include many protein-inhibitor conformations as well as monomeric and dimeric inhibitor-protein complexes, thus rendering it the largest computational study on chemical shifts of 19 F nuclei in a biological context to date. Our predicted shifts agree well with those obtained experimentally and pave the way for future work in this area.
Autoren
  • Johannes CB Dietschreit
  • Annika Wagner
  • T Anh Le
  • Philipp Klein
  • Hermann Schindelin
  • Till Opatz
  • Bernd Engels
  • Ute A Hellmich
  • Christian Ochsenfeld
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/32239740
DOI
10.1002/anie.202000539
eISSN
1521-3773
Externe Identifier
  • PubMed Central ID: PMC7496126
Ausgabe der Veröffentlichung
31
Zeitschrift
Angew Chem Int Ed Engl
Schlüsselwörter
  • African sleeping sickness
  • NMR spectroscopy
  • covalent inhibitors
  • quantum chemistry
  • structural biology
  • Enzyme Inhibitors
  • Fluorine
  • Mutation
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protozoan Proteins
  • Pyrimidinones
  • Thiophenes
  • Thioredoxins
  • Trypanocidal Agents
  • Trypanosoma brucei brucei
Sprache
eng
Country
Germany
Paginierung
12669 - 12673
Datum der Veröffentlichung
2020
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
Predicting 19 F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase-Inhibitor Complex.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
59

Datenquelle: PubMed

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