Mechanistic insights into the selectivity of bicyclophosphorothionate antagonists for housefly versus rat GABA receptors

Abstract

AbstractBACKGROUNDγ‐Aminobutyric acid (GABA) receptors (GABARs) are validated targets of insecticides. Bicyclophosphorothionates are a group of insecticidal compounds that act as noncompetitive antagonists of GABARs. We previously reported that the analogs exhibit various degrees of selectivity for housefly versus rat GABARs, depending on substitutions at the 3‐ and 4‐positions. We here sought to elucidate the unsolved mechanisms of the receptor selectivity using quantitative structure–activity relationship (QSAR), molecular docking, and molecular dynamics approaches.RESULTSThree‐dimensional (3D)‐QSAR studies using Topomer comparative molecular field analysis quantitatively demonstrated how the introduction of a small alkyl group at the 3‐position of bicyclophosphorothionates contributes to the housefly versus rat GABAR selectivity. To investigate the molecular mechanisms of the selective action, bicyclophosphorothionates were docked into housefly Resistance to dieldrin (RDL) GABAR and rat α1β2γ2 GABAR homology models built using the published 3D‐structures of human GABARs as templates. The results of molecular docking and molecular dynamics simulations revealed that the 2'Ala and 6'Thr residues of the RDL subunit within the channel are the key amino acids for binding to the housefly GABARs, whereas the 2'Ser residue of γ2 subunit plays a crucial role in binding to rat GABARs.CONCLUSIONWe revealed the molecular mechanisms underlying the selective antagonistic action of bicyclophosphorothionates on housefly versus rat GABARs. The information presented should help design and develop novel, safe GABAR‐targeting insecticides. © 2023 Society of Chemical Industry.