舞毒蛾Methuselah-like分子模拟及靶向小分子抑制剂研究  

Molecular Simulation of Lymantria dispar Methusel

作　　者：吴元旺 谢佳铭 丛培娟 曹传旺[1,3] 孙丽丽[1] WU Yuan-wang;XIE Jia-ming;CONG Pei-juan;CAO Chuan-wang;SUN Li-li(College of Forestry,Northeast Forestry University,Harbin 150040,China;Comprehensive guarantee and technology Promotion Center of People's Government of Bisiyingzi Town,Ningcheng County,Chifeng City,Inner Mongolia;Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education,Harbin 150040,China)

机构地区：[1]东北林业大学林学院,黑龙江哈尔滨150040 [2]内蒙古赤峰市宁城县必斯营子镇人民政府综合保障和技术推广中心,内蒙古赤峰024212 [3]东北林业大学森林生态系统可持续经营教育部重点实验室,黑龙江哈尔滨150040

出　　处：《林业科学研究》2024年第4期12-23,共12页Forest Research

基　　金：国家自然科学基金面上项目(32071772);中央高校基本业务费(2572022DQ04)。

摘　　要：[目的]旨在通过虚拟筛选技术筛选Methuselah-like(Ldmthl1)蛋白潜在的小分子抑制剂,并通过分子动力学模拟、MM-PBSA及生物测定,探究潜在化合物对Ldmthl1蛋白的抑制能力,为针对舞毒蛾Ldmthl1研发新型靶向杀虫剂奠定理论基础。[方法]以舞毒蛾为研究对象,构建Ldmthl1同源模型,虚拟筛选Ldmthl1受体小分子抑制剂,并采用分子动力学和MM-PBSA计算结合自由能分析6种潜在小分子抑制剂与Ldmthl1受体的结合强度;通过生物测定分析6种潜在小分子抑制剂的毒力,同时将6种潜在小分子抑制剂与溴氰菊酯进行联合使用,探究6种潜在化合物的增效作用。[结果]Ldmthl1含7个跨膜结构,符合G蛋白偶联受体结构特点,评估后符合蛋白模型评估标准;分子对接获得20个候选化合物,根据结合方式及结合能确定6种小分子化合物为潜在的抑制剂;分子动力学模拟显示,6种潜在小分子抑制剂通过氢键和疏水作用力与Ldmthl1受体稳定结合;MM-PBSA计算结合自由能发现6种潜在小分子抑制剂与Ldmthl1受体结合紧密;致死浓度LC30溴氰菊酯与6种抑制剂按照1:1、1:2和2:1的比例联合使用饲喂舞毒蛾3龄幼虫,6种抑制剂与溴氰菊酯具有协同增效作用,且当混合比例为1:2时,增效作用最显著,但溴氰菊酯浓度过高时,导致抑制剂无增效作用。[结论]虚拟筛选得到6种可与Ldmthl1受体稳定结合且具有杀虫活性潜在小分子抑制剂,与溴氰菊酯联用后呈现增效作用,本研究可为研发Ldmthl1靶向新型杀虫剂奠定理论基础。[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 inhibitors of the Ldmthl1 receptor.The binding strength of 6 potential small molecule inhibitors to Ldmthl1 receptor was analyzed by using molecular dynamics and MM-PBSA;The toxicity of 6 potential small molecule 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 evaluation 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 energies;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 receptor;The lethal concentration of LC30 deltamethrin and 6 inhibitors were combined to feed the 3rd instars of Lymantria dispar larvae at the ratio of 1:1,1:2 and 2:1.The combination of 6 inhibitors with deltamethrin 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

关 键 词：舞毒蛾 Methuselah-like 分子对接 虚拟筛选 小分子抑制剂 

分 类 号：S763.3[农业科学—森林保护学]