Molecular Simulation Of The Orthosteric Site Of Insect GABA Receptors And Their Competitive Antagonists

The?-aminobutyric acid(GABA)receptor is one of the targets for the study of pesticides.In this study,three-dimensional structures of mammalian and insect GABA receptors were constructed.Explore the mechanism of action and selectivity of GABA receptor antagonists in insects and mammals.The expected conclusions lay the theoretical foundation for the development of highly effective and low-toxic competitive antagonistic insecticides.1.Human?1?2?2 GABA receptor and housefly,Small brown planthopper,Asian cotton leafworm GABA receptor were built by homology modeling using the human GABA_A?3 receptors as a template.The stability and reliability of the model were verified by molecular dynamics and conformational analyses.2.Docking studies of three insect GABA receptors and human?1?2?2GABA receptor with the database of 3-hydroxyisoxazole/thiazole derivatives and iminopyridazine derivatives.The trend of docking and scoring is basically the same.Among them,3-hydroxyisoxazole derivatives(compound5)and iminopyridazine derivatives(compound 3)scored best for insect GABA receptors.Furthermore,these compounds have lower scores for human GABA receptors,contrary to the insect GABA receptor trends described above,suggesting that these two types of GABA receptor competitive antagonists are selective between mammals and insects.The above docking scores are basically in line with the results of biological activity tests.3.By molecular docking,compound 3 and compound 5 bind to three insect GABA receptors and are both stable in conformation and energy.At the same time,it binds to insect GABA receptors in a dominant binding mode,and the binding modes are basically similar.Through comparative analysis of free energy,hydrogen bonding,electrostatic interaction,and hydrophobic interaction,Glu148,Ser149,and Phe150 in loop B,Thr194 and Tyr198 in loop C,and Tyr53 and Arg55 in loop D were found to be the key amino acids.The naphthyl group at the 3 position of the azine ring of compound 3 was found.The carboxyl group at position 1 was the key characteristic structure,and it was easy to interact with the nearby amino acids.Compound 5 oxazole ring 4-position biphenyl,5-carbamoyl is a key feature.The binding patterns of compound 3 and compound 5 to human GABA receptors indicate that the above characteristic amino acid residues are located far from the ligand or form weak hydrogen-bond interactions.Therefore,the analysis results revealed that the GABA receptor CAs 3-hydroxyisoxazole/thiazole derivatives and iminophthalazine derivatives characteristic structure and interaction of key amino acids...