The Study Of Structure-activity Relationship And Molecular Mechanism Of Resistance Of Novel Pyrethroids Based On Molecular Simulation

Aedes albopictus is the main vector of dengue fever,chikungunya and Zika virus,and is the sole vector for dengue transmission in southern China.At present,the main method to prevent the transmission of dengue fever in China is to use pyrethroids to control the vectors.However,due to excessive and inappropriate use of pyrethroids,mosquitoes have developed resistance to pyrethroids.There are two main pyrethroids resistance in Aedes albopictus,including metabolic resistance which is mainly enhanced by cytochrome P450monooxygenase detoxification and target resistance that pyrethroid insecticides exert their toxic effects by prolonging the opening time of voltage-sensitive sodium channels（VSSC）.The VSSC binding site mutation in Aedes albopictus reduces binding and produces resistance.Here,the quantitative structure-activity relationship of novel pyrethroid compounds was studied,and the novel pyrethroid compounds and target were used to molecular docking to understand the molecular interaction mechanism at the molecular level,which provided a theoretical basis for the design of new and effective pyrethroid compounds.The main research contents and results are as follows:（1）The 2D-QSAR of 74 novel pyrethroids was studied using multiple linear regression,partial least squares regression based on R language,but the obtained model is poor.Novel pyrethroids was further studied by 3D-QSAR methods（Co MFA,Co MSIA）.The results show that the two models of correlation and prediction are excellent.By analyzing contour maps of the two models,it was found that introducing a large group or strong hydrophilic group at the position of R₃,a positively charged or hydrophobic group at the substituents R₁ and R₂,a positively charged group at the position of R₅,and a hydrogen bond donor group at the group of R₄ were beneficial to the improvement of the activity of the compounds.（2）The three-dimensional structure of sodium channel,CYP4H43 and CYP6N3v1proteins of Aedes albopictus were constructed by homology modeling.And then structure of proteins were verified by Pro SA and ramachandran plot,etc.The results showed that the constructed models were reasonable and reliable.（3）Based on Vina,Auto Dock and Surflex-Dock,the three-dimensional structure obtained from homology modeling were docked with 74 novel pyrethroids.By analyzing the docking sore with the p IC₅₀,it was found that the binding free energy was negatively correlated with the p IC₅₀.By analyzing the molecular interaction between the sodium ion channel and the novel pyrethroid compounds,it was found that the novel pyrethroid compounds had salt bridge interaction with LYS-1279 of sodium channel.And the novel pyrethroid compounds have hydrophobic interaction and halogen bond interaction with SER-989 and ASN-1325respectively.Which is fixed novel pyrethroids compounds to sodium channels open state,causing sodium channels open time delay and insects paralysis condition until death.By analyzing the binding pattern of CYP4H43 and the novel pyrethroid compounds,it was found that compound 36 have P-πstair interaction with CYP4H43,which could keep benzene ring away from the heme catalytic center.Compound 11 have bromine atomic structure of dihaloethylene of deltamethrin,and also formed hydrogen bond interaction with GLU-77 and GLN-24 of CYP4H43,which could stabilize the compound and keep it away from the heme catalytic center.Therefore,compounds 36 and 11 may bind to P450,but cannot be metabolized by P450 and may be used as potential new insecticides.（4）100 ns molecular dynamics simulation was performed for CYP4H43,CYP4H43＿11,CYP4H43＿19,CYP4H43＿23,CYP4H43＿29 and CYP4H43＿36 complexes.During the simulation,the number of hydrogen bonds between compound 11 and CYP4H43 fluctuated between 2 and 3,but there was a stable hydrogen bond all the time,indicating that the complex CYP4H43＿11 was stable.Finally,the MMPBSA was used to calculate the binding free energy of the five complexes and the energy decomposition was carried out.The results showed that van der Waals energy（VDW）,electrostatic energy（△Eele）and non-polar solvation free energy（△Gnonpolar）played a promoting role in the process of small molecule drug binding proteins.Polar solvation free energy（△Gpolar）and entropy contribution（-T△S）repelled the binding of small drug molecules to protein.