小分子PB2蛋白抑制剂的虚拟筛选及初步活性研究

Virtual screening of small molecule inhibitors targeting PB2 protein and study of the preliminary bioactivity

目的通过药效团模型和分子对接筛选具有新型骨架的PB2蛋白抑制剂,并初步研究其活性。方法利用HipHop程序建立PB2蛋白抑制剂的药效团模型,并利用该模型筛选Chemdiv数据库;对匹配较好的化合物利用CDOCKER进行筛选排序,挑选排序靠前的6个化合物,通过差示扫描量热法和Biacore体外活性测试方法进行生物活性验证;利用分子对接预测CD419与PB2蛋白的相互作用模式。结果得到了1个活性较好的新骨架结构化合物CD419。该化合物的温度偏移ΔTm为4.89℃;Biacore结果显示其KD值为60μmol·L^(-1)。结论获得了一个作用于PB2蛋白的全新骨架结构活性小分子化合物,为靶向PB2蛋白的抗流感药物研发提供了良好的先导化合物。

OBJECTIVE To screen for PB2 protein inhibitors with new scaffolds by pharmacophore modeling and molecular docking,and to study their bioactivities. METHODS Firstly,a pharmacophore model of PB2 protein inhibitors was established using the Hip Hop program,and then this pharmacophore model was applied to screen Chemdiv database. For compounds matched well with the pharmacophore model,CDOCKER was used to further sort them. Next,the in vitro bioactivity validation of six top ranked compounds were performed by DSF and Biacore assays. Finally,we predicted the binding mode between CD419 and PB2 protein by utilizing molecular docking. RESULTS CD419,containing a new scaffold,was obtained,which showed a ΔTm value of4. 89 ℃ in DSF assay and KD value of 60 μmol·L^(-1) in Biacore assay. CONCLUSION A new PB2 protein inhibitor with a novel scaffold was obtained. This study provides a good lead compound for later anti-influenza drug discovery targeting PB2 protein.