Neonicotinoids represent a widely used group of pesticides that share the same target as nicotine. Initially they were designed to achieve selective toxicity on insect receptors. However, concerns arose regarding low mammalian toxicity, especially concerning metabolites that could be formed during both, environmental breakdown and mammalian metabolism. In order to assess their potential developmental neurotoxicity (DNT) hazard for humans, a subgroup of neonicotinoids and a major metabolite Desnitro-Imidacloprid was already tested on human neurons. Additionally, key molecular initiating event (MIE) interactions, represented as binding to nAChRs, were identified by molecular docking in our previous study.<br/>As an extension to that, the chemical space was broadened by including other neonicotinoid analogues, nicotinoids, and relevant metabolites of Imidacloprid, Thiacloprid and Acetamiprid. The focus of the structure-based investigations lies on major isoforms of the nAChR that are expressed in the human brain, namely α7, α3β4 and α4β2. Therefore, recently published cryo-EM-structures that show different protein conformations, are included for every subtype. A molecular docking workflow combined with subsequent calculations for an estimate of respective binding energies were used in this study. Finally, the protein ligand interaction fingerprints are generated and used for clustering and further analysis. Depending on the isoform and conformation of the protein, as well as respective ligand properties, different interactions can be formed within the binding site.

Exploration of potential MIE interactions of neonicotinoid pesticides and relevant metabolites by molecular docking to human nicotinic acetylcholine receptors (nAChRs)

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