昆虫章鱼胺受体激动剂亚氨基杂环类化合物的构效关系与药效团研究

Structure-Activity Relationship and Pharmacophore Study of Imino-Heterocyclic Compounds as Agonists of Insect Octopamine Receptors

昆虫章鱼胺受体(OAR)属于G蛋白偶联受体,是一类重要的杀虫剂靶标。基于美洲蟑螂OAR激动剂2-芳基亚氨基杂环类化合物的分子结构和生物活性,运用分子模拟的方法构建了该类化合物的三维定量构效关系(3D-QSAR)和药效团模型,系统分析了该类化合物作为OAR激动剂的构效关系。内外部参数均验证了3D-QSAR模型的可靠性和良好的预测能力;通过对3D-QSAR模型等势图分析发现,在苯环的环取代邻位引入体积较大的正电子基团和在苯环的环取代对位引入负电子基团都有可能提高该类化合物的活性;通过对药效团模型分析发现,所构建的最佳药效团模型是合理的,苯环和杂环作为2个疏水中心、2个氮原子作为2个正电中心可能与该类化合物对OAR产生活性具有重要作用。该研究结果为靶向OAR杀虫剂的设计和开发提供了重要信息。

Insect octopamine receptors(OAR)are an important class of insecticide targets,which belong to G protein-coupled receptors.On the basis of the molecular structure and biological activity of Periplaneta americana OAR agonists,namely,2-aryliminoheterocyclic derivatives,we constructed the three-dimensional quantitative structure-activity relationships(3D-QSAR)and pharmacophore models of these compounds by molecular simulation.Moreover,we systematically analyzed the structure-activity relationship of these compounds as OAR agonists.Both internal and external parameters verify the reliability and good prediction ability of 3D-QSAR model.Through the analysis of contour maps of 3D-QSAR model,it is found that the introduction of larger positron groups in the ortho position of ring-substituted groups of benzene ring and negative electron groups in the para position of ring-substituted groups of benzene ring may enhance the activity of these compounds.Meanwhile,through the analysis of pharmacophore model,it is found that the best pharmacophore model is reasonable.Benzene ring and heterocycle(as two hydrophobic centers)and two nitrogen atoms(as two positive centers)may play important roles in the OAR activity of these compounds.The results provide important information for the design and development of targeted OAR insecticides.