Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging

Lade...
Vorschaubild
Dateien
Grillberger_2-1fuv8bigj09r25.pdf
Grillberger_2-1fuv8bigj09r25.pdfGröße: 2.11 MBDownloads: 13
Datum
2023
Herausgeber:innen
Kontakt
ISSN der Zeitschrift
Electronic ISSN
ISBN
Bibliografische Daten
Verlag
Schriftenreihe
Auflagebezeichnung
ArXiv-ID
Internationale Patentnummer
Link zur Lizenz
Angaben zur Forschungsförderung
European Union (EU): 964537
Projekt
RISK-HUNT3R
Open Access-Veröffentlichung
Open Access Gold
Sammlungen
Core Facility der Universität Konstanz
Gesperrt bis
Titel in einer weiteren Sprache
Forschungsvorhaben
Organisationseinheiten
Zeitschriftenheft
Publikationstyp
Zeitschriftenartikel
Publikationsstatus
Published
Erschienen in
International Journal of Molecular Sciences. MDPI. 2023, 24(17), 13170. ISSN 1661-6596. eISSN 1422-0067. Available under: doi: 10.3390/ijms241713170
Zusammenfassung

Neonicotinoid pesticides were initially designed in order to achieve species selectivity on insect nicotinic acetylcholine receptors (nAChRs). However, concerns arose when agonistic effects were also detected in human cells expressing nAChRs. In the context of next-generation risk assessments (NGRAs), new approach methods (NAMs) should replace animal testing where appropriate. Herein, we present a combination of in silico and in vitro methodologies that are used to investigate the potentially toxic effects of neonicotinoids and nicotinoid metabolites on human neurons. First, an ensemble docking study was conducted on the nAChR isoforms α7 and α3β4 to assess potential crucial molecular initiating event (MIE) interactions. Representative docking poses were further refined using molecular dynamics (MD) simulations and binding energy calculations using implicit solvent models. Finally, calcium imaging on LUHMES neurons confirmed a key event (KE) downstream of the MIE. This method was also used to confirm the predicted agonistic effect of the metabolite descyano-thiacloprid (DCNT).

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
Schlagwörter
neonicotinoids, pesticides, metabolites, nAChR, docking, molecular dynamics simulations, calcium imaging
Konferenz
Rezension
undefined / . - undefined, undefined
Zitieren
ISO 690GRILLBERGER, Karin, Eike CÖLLEN, Claudia Immacolata TRIVISANI, Jonathan BLUM, Marcel LEIST, Gerhard F. ECKER, 2023. Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging. In: International Journal of Molecular Sciences. MDPI. 2023, 24(17), 13170. ISSN 1661-6596. eISSN 1422-0067. Available under: doi: 10.3390/ijms241713170
BibTex
@article{Grillberger2023-08-24Struc-67829,
  year={2023},
  doi={10.3390/ijms241713170},
  title={Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging},
  number={17},
  volume={24},
  issn={1661-6596},
  journal={International Journal of Molecular Sciences},
  author={Grillberger, Karin and Cöllen, Eike and Trivisani, Claudia Immacolata and Blum, Jonathan and Leist, Marcel and Ecker, Gerhard F.},
  note={Article Number: 13170}
}
RDF
<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/67829">
    <dc:language>eng</dc:language>
    <dc:rights>Attribution 4.0 International</dc:rights>
    <dcterms:title>Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging</dcterms:title>
    <dc:creator>Cöllen, Eike</dc:creator>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2023-09-20T08:26:37Z</dc:date>
    <dc:creator>Grillberger, Karin</dc:creator>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2023-09-20T08:26:37Z</dcterms:available>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dc:creator>Trivisani, Claudia Immacolata</dc:creator>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/67829/1/Grillberger_2-1fuv8bigj09r25.pdf"/>
    <dc:contributor>Blum, Jonathan</dc:contributor>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/67829/1/Grillberger_2-1fuv8bigj09r25.pdf"/>
    <dcterms:rights rdf:resource="http://creativecommons.org/licenses/by/4.0/"/>
    <dc:contributor>Grillberger, Karin</dc:contributor>
    <dc:creator>Leist, Marcel</dc:creator>
    <dc:creator>Blum, Jonathan</dc:creator>
    <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/67829"/>
    <dc:creator>Ecker, Gerhard F.</dc:creator>
    <dcterms:issued>2023-08-24</dcterms:issued>
    <dc:contributor>Cöllen, Eike</dc:contributor>
    <dc:contributor>Trivisani, Claudia Immacolata</dc:contributor>
    <dc:contributor>Leist, Marcel</dc:contributor>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dcterms:abstract>Neonicotinoid pesticides were initially designed in order to achieve species selectivity on insect nicotinic acetylcholine receptors (nAChRs). However, concerns arose when agonistic effects were also detected in human cells expressing nAChRs. In the context of next-generation risk assessments (NGRAs), new approach methods (NAMs) should replace animal testing where appropriate. Herein, we present a combination of in silico and in vitro methodologies that are used to investigate the potentially toxic effects of neonicotinoids and nicotinoid metabolites on human neurons. First, an ensemble docking study was conducted on the nAChR isoforms α7 and α3β4 to assess potential crucial molecular initiating event (MIE) interactions. Representative docking poses were further refined using molecular dynamics (MD) simulations and binding energy calculations using implicit solvent models. Finally, calcium imaging on LUHMES neurons confirmed a key event (KE) downstream of the MIE. This method was also used to confirm the predicted agonistic effect of the metabolite descyano-thiacloprid (DCNT).</dcterms:abstract>
    <dc:contributor>Ecker, Gerhard F.</dc:contributor>
  </rdf:Description>
</rdf:RDF>
Interner Vermerk
xmlui.Submission.submit.DescribeStep.inputForms.label.kops_note_fromSubmitter
Kontakt
URL der Originalveröffentl.
Prüfdatum der URL
Prüfungsdatum der Dissertation
Finanzierungsart
Kommentar zur Publikation
Allianzlizenz
Corresponding Authors der Uni Konstanz vorhanden
Internationale Co-Autor:innen
Universitätsbibliographie
Ja
Begutachtet
Ja
Diese Publikation teilen