2026-10-11T17:51:56Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34040250 2026-10-01T06:05:05Z category_1 category_4 category_12 category_13 category_14 category_15 category_19 category_24 category_873 category_106 category_135 portal_63 item_type_6 month_year_10_2026

Structural Modifications Redirect Phenylpyrazole Ectoparasiticides from the Ion Channel Pore to an Allosteric Site on GABA Receptors Tianhao Zhou (6095903) Zihan Cheng (5713415) Honglei Xie (3162414) Ailing Liu (119500) Shoujun Li (572627) Xiaomu Qiao (656142) Jia Huang (42138) Biophysics Biochemistry Cell Biology Genetics Molecular Biology Neuroscience Pharmacology Evolutionary Biology Chemical Sciences not elsewhere classified Science Policy Computational Biology targeted insecticide design pharmacological assays showed molecular docking supported arthropod gaba receptors traditional pore blockers ion channel pore molecular mechanism gaba receptor central pore structural modification site engagement results demonstrate redirect target phenylpyrazole scaffold noncompetitive antagonists nicofluprole sensitivity nicofluprole binds mediated mutagenesis little effect g335 mutations expanding strategies allosteric site allosteric modulation a301 substitutions Phenylpyrazole ectoparasiticides, exemplified by fipronil, act as noncompetitive antagonists of arthropod GABA receptors by blocking the ion channel pore. Here, we investigated the molecular mechanism of the newer phenylpyrazole nicofluprole using Drosophila melanogaster. CRISPR/Cas9-mediated mutagenesis and pharmacological assays showed that A301 substitutions in the pore-forming TM2 helix conferred strong resistance to fipronil but had little effect on nicofluprole sensitivity. In contrast, G335 mutations in TM3 markedly reduced nicofluprole activity. Molecular docking supported these findings, indicating that nicofluprole binds at the transmembrane subunit interface rather than within the central pore, consistent with allosteric modulation. These results demonstrate that structural modification of the phenylpyrazole scaffold can redirect target-site engagement from the pore to an allosteric site, explaining the lack of cross-resistance with traditional pore blockers and expanding strategies for GABA receptor-targeted insecticide design. 2026-10-01T00:00:00Z Text Journal contribution 10.1021/acs.jafc.6c09630.s001 https://figshare.com/articles/journal_contribution/Structural_Modifications_Redirect_Phenylpyrazole_Ectoparasiticides_from_the_Ion_Channel_Pore_to_an_Allosteric_Site_on_GABA_Receptors/34040250 CC BY-NC 4.0