Design and activity validation of GABA-gated chloride channels allosteric modulators based on computational biology

Ionotropic γ-aminobutyric acid (GABA) receptors are the predominant inhibitory neurotransmitter receptors in the insect nervous system and serve as critical targets for insecticides. Meta-diamide insecticides exert their effects by binding to GABA receptors, inhibiting chloride ion influx, causing insects excited and convulsed, ultimately leading to death. To develop novel insecticides with enhanced bioactivity, this study selected broflanilide as a lead compound and employed scaffold hopping and substituent modification strategies to design and synthesize a series of meta-diamide derivatives containing cycloalkanes. Preliminary assays indicated that some compounds exhibited promising insecticidal effects against Plutella xylostella. Compound T-10 displayed median lethal concentration (LC₅₀) value of 0.004 mg/L, which was comparable to broflanilide (LC₅₀ = 0.009 mg/L). Molecular docking confirmed that descyclopropylmethyl-T-10 and desmethyl-broflanilide exhibited similar binding modes at the active site of the GABA receptor in Drosophila melanogaster. Molecular dynamics simulations further validated the stable binding of descyclopropylmethyl-T-10 to the GABA receptor, demonstrating its strong inhibitory effect. Density Functional Theory (DFT) calculation indicated a negative correlation between the HOMO-LUMO gap values (ΔE) of desmethyl-broflanilide and descyclopropylmethyl-T-10 and their bioassay results. This study provides a promising compound structure as a novel meta-diamide lead compound to control Plutella xylostella.