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Insight into the Binding Mode of Agonists of the Nicotinic Acetylcholine Receptor from Calculated Electron Densities
Author(s) -
Beck Michael E.,
Gutbrod Oliver,
Matthiesen Svend
Publication year - 2015
Publication title -
chemphyschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.016
H-Index - 140
eISSN - 1439-7641
pISSN - 1439-4235
DOI - 10.1002/cphc.201500341
Subject(s) - nicotinic agonist , mode of action , nicotinic acetylcholine receptor , acetylcholine receptor , homology modeling , receptor , chemistry , binding site , rational design , biophysics , stereochemistry , computational biology , biology , biochemistry , genetics , enzyme
Insect nicotinic acetylcholine receptors ( n AChRs) are among the most prominent and most economically important insecticide targets. Thus, an understanding of the modes of binding of respective agonists is important for the design of specific compounds with favorable vertebrate profiles. In the case of n AChRs, the lack of available high‐resolution X‐ray structures leaves theoretical considerations as the only viable option. Starting from classical homology and docking approaches, binding mode hypotheses are created for five agonists of the n AChR, covering insecticides in the main group 4 of the Insecticide Resistance Action Committee (IRAC) mode of action (MoA) classification, namely, neonicotinoids, nicotine, sulfoxaflor, and butenolides. To better understand these binding modes, the topologies of calculated electron densities of small‐model systems are analyzed in the framework of the quantum theory of atoms in molecules. The theoretically obtained modes of binding are very much in line with the biology‐driven IRAC MoA classification of the investigated ligands.