Grillberger, K.; Cöllen, E.; Trivisani, C.I.; Blum, J.; Leist, M.; Ecker, G.F. Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging. Int. J. Mol. Sci. 2023, 24, 13170.
DOI
https://doi.org/10.3390/ijms241713170
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).
Funding
This work was funded by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 964537 (RiskHunt3R), which is part of the ASPIS cluster.
Rights & permissions
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
© 2023 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
neonicotinoids; pesticides; metabolites; nAChR; docking; molecular dynamics simulations; calcium imaging
