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Exploring the Interaction Mechanism of Desmethyl-broflanilide in Insect GABA Receptors and Screening Potential Antagonists by In Silico Simulations.
- Source :
-
Journal of agricultural and food chemistry [J Agric Food Chem] 2020 Dec 16; Vol. 68 (50), pp. 14768-14780. Date of Electronic Publication: 2020 Dec 04. - Publication Year :
- 2020
-
Abstract
- Broflanilide, a novel insecticide, is classified as a negative allosteric modulator (NAM) of insect γ-aminobutyric acid (GABA) receptors (GABARs) as desmethyl-broflanilide (DMBF) allosterically inhibits the GABA-induced responses. The G277M mutation of the Drosophila melanogaster GABAR subunit has been reported to abolish the inhibitory activity of DMBF. The binding mode of DMBF in insect GABARs needs to be clarified to understand the underlying mechanism of this mutation and to develop novel, efficient NAMs of insect GABARs. Here, we found that a hydrogen bond formed between DMBF and G277 of the D. melanogaster GABAR model might be the key interaction for the antagonism of DMBF by in silico simulations. The volume increase induced by the G277M mutation blocks the entrance of the binding pocket, making it difficult for DMBF to enter the binding pocket and thereby decreasing its activity. The following virtual screening and bioassay results identified a novel NAM candidate of insect GABARs. Overall, we reported a possible binding mode of DMBF in insect GABARs and proposed the insensitivity mechanism of the G277M mutant GABAR to DMBF using molecular simulations. The identified NAM candidates might provide more alternatives or potentials for the design of GABAR-targeting insecticides.
- Subjects :
- Animals
Benzamides metabolism
Benzamides pharmacology
Computer Simulation
Drosophila Proteins antagonists & inhibitors
Drosophila Proteins genetics
Drosophila melanogaster chemistry
Drosophila melanogaster drug effects
Drosophila melanogaster genetics
GABA Antagonists metabolism
GABA Antagonists pharmacology
Molecular Docking Simulation
Receptors, GABA genetics
Benzamides chemistry
Drosophila Proteins chemistry
Drosophila Proteins metabolism
Drosophila melanogaster metabolism
GABA Antagonists chemistry
Receptors, GABA chemistry
Receptors, GABA metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-5118
- Volume :
- 68
- Issue :
- 50
- Database :
- MEDLINE
- Journal :
- Journal of agricultural and food chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33274636
- Full Text :
- https://doi.org/10.1021/acs.jafc.0c05728