Homo- and hetero-dimers of inactive organophosphorous group binding at dual sites of AChE

Homo- and hetero-dimers of inactive organophosphorous group(s) dramatically enhanced the acetylcholinesterase (AChE; EC 3.1.1.7) inhibiting potency, with the highest potency observed at a tether length of 6 methylene groups (6d) for the homodimers, and 7 methylene groups (8e) for the heterodimers. The docking model of Drosophila melanogaster AChE suggested that 6d and 8e bound at the catalytic and peripheral sites of AChE, in which two organophosphorous groups of 6d individually oriented towards TRP83 of catalytic sites and TRP321 of peripheral sites, and phthalicimide group of 8e was appropriately arranged for a π–π interaction with the phenyl ring of TYR330, furthermore, the organophosphorous group introduced hydrophobic interaction with TRP83. The compounds prepared in this work demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnbarinus at the concentration 300 mg/L.

Hypothetical binding mode between 6d (carbon in green, oxygen in red, phosphorus in purple and sulfur in yellow) and the DmAChE active site gorge (only a few amino acid residues are shown for clarity).Hypothetical binding mode between 8e (carbon in green, oxygen in red, phosphorus in purple and sulfur in yellow) and the DmAChE active site gorge (only a few amino acid residues are shown for clarity).Figure optionsDownload as PowerPoint slide