基于分子对接的DNA拓扑异构酶Ⅳ抑制剂的虚拟筛选研究

Virtual Screening of DNA TopoisomeraseⅣInhibitors Based on Molecular Docking

目的基于分子对接的虚拟筛选和体外抑菌实验快速筛选出DNA拓扑异构酶Ⅳ抑制剂。方法采用AutoDock Vina程序对DNA拓扑异构酶Ⅳ的3个靶点蛋白1S16、3FV5和4ZH0进行方法学研究,通过均方根偏差(RMSD)、曲线下面积(AUC)、富集因子(EF)等参数评估对活性分子富集能力较强的分子对接模型,并利用该模型对数据库进行大规模的虚拟筛选,保留结合能低于阈值的化合物开展体外抑菌实验。结果综合回溯性验证结果发现1S16靶点蛋白的分子对接模型具有较强的活性分子富集能力,基于该模型虚拟筛选出22个具有潜在抑菌活性的化合物,体外抑菌实验发现其中8个化合物具有明显的抗大肠杆菌活性。结论本研究发现8个化合物具有明确的抗大肠杆菌活性,有望成为新型DNA拓扑异构酶Ⅳ抑制剂。

OBJECTIVE To screen DNA topoisomeraseⅣinhibitors by virtual screening based on molecular docking and in vitro bacteriostatic test.METHODS Methodological research was performed to study the target proteins of 1S16,3FV5 and 4ZH0 of DNA topoisomeraseⅣthrough the AutoDock Vina program.The molecular docking models with strong enrichment ability for active molecules were evaluated by parameters of RMSD,AUC and EF value,and the model was used to conducte large-scale virtual screening of the database.Compounds with binding energy below the threshold value were retained for in vitro bacteriostatic test.RESULTS Based on the comprehensive retrospective verification results,it was found that the molecular docking model of the 1S16 target protein had a strongest ability to enrich active molecules.Based on this model,22 compounds with potential bacteriostatic activity were virtually screened,and 8 of them were found to have obvious anti-Escherichia coli activity in vitro bacteriostatic test.CONCLUSION In this study,the theoretical calculation method combined with the experimental results showed that 8 compounds have clear anti-Escherichia coli activity,which are expected to be the novel DNA topoisomeraseⅣinhibitors.