Study Of The Interaction Between Avermectins And Glutamate Receptors Of Flies

Avermectin with high efficiency, low toxicity and the widely insecticidal characteristics is widely used in the agricultural pesticides. But, the potential harm is slowly shown with the abuse of such drugs. For example, the gradually increased insect resistance leads to the gradually reduced efficacy of avermectin, so the fast and high efficient design of novel avermectin derivatives becomes the scientists’ goal. The new drug design must be based on a clear mechanism of drug action. The glutamate receptor in agricultural pests is usually identified as the target protein of avermectin. This article aims to reveal the interaction mechanism between glutamate receptor and avermectin in the molecular level, which will lay the theoretical foundation for the design of novel avermectin derivatives.The five α-glutamate receptors of Drosophila melanogaster (F、B、C、D、A) and a α-glutamate receptor of Musca domestica or Lucilia cuprina are modeled with 3RHW of Caenorhabditis elegans in protein database as the template, and through assessment of Ramachandran plot and main chain and side chain of the seven kinds of receptors, we found that the percentage of amino acid residues of all glutamate receptors in reasonable regional are higher than the standard requirements of 90%, and the modeled receptor structure is similar as the already-known protein structure, which indicate that the constructed receptors are reasonable, and can be used for the next docking experiments.Then, the molecular docking studies on all of α-glutamate receptors with avermectin, ivermectin, doramectin and milbemcycin were investigated with Surflex-Dock module of Sybyll.1 software, respectively. (1) the order of toxicity between four drugs and the different subtypes of α-glutamate receptor of drosophila demonstrate is F>C>B>D>A for avermectin, C>F>B>D>A for ivermectin, F >C>B>D>A for doramectin and D> C> F> B> A for milbemcycin; (2) the results of the interactions between four drugs and three kinds of insects show that the toxicity order is almost the same for Drosophila melanogaster, Musca domestica and Lucilia cuprina:avermectin> doramectin> ivermectin> milbemcycin, and the affinity of avermectin with the five a-glutamate receptors of Drosophila melanogaster and a a-glutamate receptor of Musca domestica or Lucilia cuprina is strongest compared with one of the other drugs. For Drosophila melanogaster, the free binding energy between avermectin and GluCl-α in Drosophila melanogaster is-7.618 Kcal mol-1,-7.427 Kcal mol-1 between doramectin and Drosophila melanogaster,-6.311 Kcal mol-1 between ivermectin and Drosophila melanogaster and -5.883 Kcal mol-1 between milbemcycin and Drosophila melanogaster, which is consistent with the experimental results that the toxicity of avermectin is highest in Drosophila melanogaster. For Musca domestica,-6.738 Kcal mol-1 between avermectin and Musca domestica,-5.363 Kcal mol-1 between doramectin and Musca domestica,-4.356 Kcal moF1 between ivermectin and Musca domestica and -3.867 Kcal mol-1 between milbemcycin and Musca domestica. For Lucilia cuprina,-5.459 Kcal mol-1 between avermectin and Lucilia cuprina,-4.138 Kcal mol-1 between doramectin and Lucilia cuprina,-3.852 Kcal mol-1 between ivermectin and Lucilia cuprina and -3.389 Kcal mol-1 between milbemcycin and Lucilia cuprina. (3) the strong and weak order of the interactions between three kinds of insects and avermectin derivatives is Drosophila melanogaster> Musca domestica> Lucilia cuprina.Generally, the power of toxicity for the same avermectin derivatives is different to the diverse insects with glutamate receptors assembled of the same subunit. Also the power of toxicity for the same avermectin derivatives is different to the same insects with glutamate receptors with the different subtype assembled of the same subunit.