Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging
- Author(s)
- Karin Grillberger, Eike Cöllen, Claudia Immacolata Trivisani, Jonathan Blum, Marcel Leist, Gerhard Ecker
- 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).
- Organisation(s)
- Department of Pharmaceutical Sciences
- External organisation(s)
- Universität Konstanz
- Journal
- International Journal of Molecular Sciences
- Volume
- 24
- ISSN
- 1422-0067
- DOI
- https://doi.org/10.3390/ijms241713170
- Publication date
- 08-2023
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301207 Pharmaceutical chemistry, 301211 Toxicology
- Keywords
- ASJC Scopus subject areas
- Molecular Biology, Spectroscopy, Catalysis, Inorganic Chemistry, Computer Science Applications, Physical and Theoretical Chemistry, Organic Chemistry
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/structural-insights-into-neonicotinoids-and-nunsubstituted-metabolites-on-human-nachrs-by-molecular-docking-dynamics-simulations-and-calcium-imaging(6e44de17-6497-409b-98d1-d2c26d55aae4).html