Molecular Simulation of Lymantria dispar Methuselah-like and Targeting Small Molecular Inhibitors
[Objective]The aim is to screen potential small molecule inhibitors of methuselah-like(Ldmthl1)protein through virtual screening technology and explore the inhibitory ability of potential compounds on Ldmthl1 protein through molecular dynamics simulation,MM-PBSA,and bioassays.It lays a theoretical foundation for developing new insecticides targeting Lymantria dispar Ldmthl1.[Method]The homology model of Ldmthl1 receptor was constructed in Lymantria dispar for virtual screening the small molecule in-hibitors of the Ldmthl1 receptor.The binding strength of 6 potential small molecule inhibitors to Ldmthl1 re-ceptor was analyzed by using molecular dynamics and MM-PBSA;The toxicity of 6 potential small mo-lecule inhibitors was analyzed by bioassay,and the synergistic effect of the six potential compounds was explored by combining them with deltamethrin.[Result]Ldmthl1 contained 7 transmembrane structures,which was consistent with the structural characteristics of G protein-coupled receptors,and met the evalu-ation criteria of protein models;20 candidate compounds were obtained by molecular docking,and 6 small molecule compounds were identified as potential inhibitors based on the binding models and binding ener-gies;Molecular dynamics simulations showed that 6 potential small molecule inhibitors were stably bound to Ldmthl1 receptors through hydrogen bonding and hydrophobic forces;The MM-PBSA calculation of binding free energy revealed that 6 potential small molecule inhibitors were tightly bound to the Ldmthl1 re-ceptor;The lethal concentration of LC30 deltamethrin and 6 inhibitors were combined to feed the 3rd in-stars of Lymantria dispar larvae at the ratio of 1:1,1:2 and 2:1.The combination of 6 inhibitors with del-tamethrin showed synergistic effect,and the synergistic effect was most significant when the mixing ratio was 1:2.However,no synergistic effect was found when the concentration of deltamethrin was too high.[Conclusion]Six potential small molecule inhibitors with insecticidal activity that can stably bind to the Ld-mthl1 receptor were obtained through virtual screening.They showed synergistic effects when combined with cypermethrin.This study can lay a theoretical foundation for the development of new insecticides tar-geting Ldmthl1.
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