Titel
Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging
Autor*in
Claudia Immacolata Trivisani
Department of Biotechnology, Chemistry and Pharmacy, University of Siena
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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).
Stichwort
neonicotinoidspesticidesmetabolitesnAChRdockingmolecular dynamics simulationscalcium imaging
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
International Journal of Molecular Sciences
Band
24
Ausgabe
17
ISSN
1422-0067
Erscheinungsdatum
2023
Publication
MDPI AG
Projekt
Kod / Identifikator
964537
Fördergeber
Erscheinungsdatum
2023
Zugänglichkeit
Rechte
Rechteangabe
© 2023 by the authors
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