Title of her Thesis: Structural modelling of molecular initiating event interactions: Docking neonicotinoids into human nAChR
The topic of the master thesis is related to the EU-ToxRisk project which implemented a case study about a major group of pesticides, namely neonicotinoids, in order to assess their potential developmental neurotoxicity (DNT) liabilities on humans. The underlying working hypothesis of the case study comprises an adverse outcome pathway that starts with a molecular initiating event (MIE) leading to several key events, and finally to an adverse outcome: DNT. We were focusing on the MIE on nicotinic acetylcholine receptors (nAChR), which was modelled by molecular docking of neonicotinoids and a nicotinoid metabolite into structures of the most abundant isoforms in the human brain. Subsequent analysis revealed distinct binding modes and interactions within the binding site of the target protein, that serve as structural explanations for the subgrouping of some experimentally tested neonicotinoids and their more potent nicotinoid metabolite.
Associated Publications:
(1) Loser, D.; Hinojosa, M. G.; Blum, J.; Schaefer, J.; Brüll, M.; Johansson, Y.; Suciu, I.; Grillberger, K.; Danker, T.; Möller, C.; Gardner, I.; Ecker, G. F.; Bennekou, S. H.; Forsby, A.; Kraushaar, U.; Leist, M. Functional Alterations by a Subgroup of Neonicotinoid Pesticides in Human Dopaminergic Neurons. Arch. Toxicol. 2021. https://doi.org/10.1007/s00204-021-03031-1.
(2) Loser, D.; Grillberger, K.; Hinojosa, M. G.; Blum, J.; Haufe, Y.; Danker, T.; Johansson, Y.; Möller, C.; Nicke, A.; Bennekou, S. H.; Gardner, I.; Bauch, C.; Walker, P.; Forsby, A.; Ecker, G. F.; Kraushaar, U.; Leist, M. Acute Effects of the Imidacloprid Metabolite Desnitro-Imidacloprid on Human NACh Receptors Relevant for Neuronal Signaling. Arch. Toxicol. 2021. https://doi.org/10.1007/s00204-021-03168-z.
