Pharmacophore modelling, virtual screening and molecular docking studies on PLD1 inhibitors

Lipid metabolism plays a significant role in influenza virus replication and subsequent infection. The regulatory mechanism governing lipid metabolism and viral replication is not properly understood to date, but both Phospholipase D (PLD1 and PLD2) activities are stimulated in viral infection. <i>In vitro</i> studies indicate that chemical inhibition of PLD1 delays viral entry and reduction of viral loads. The current study reports a three-dimensional pharmacophore model based on 35 known PLD1 inhibitors. A sub-set of 25 compounds was selected as the training set and the remaining 10 compounds were kept in the test set. One hundred and twelve pharmacophore models were generated; a six-featured pharmacophore model (AADDHR.57) with survival score (2.69) produced a statistically significant three-dimensional quantitative structure–activity relationship model with <i>r</i>² = 0.97 (internal training set), <i>r</i>² = 0.71 (internal test set) and <i>Q</i>² = 0.64. The predictive power of the pharmacophore model was validated with an external test set (<i>r</i>² = 0.73) and a systematic virtual screening work-flow was employed showing an enrichment factor of 23.68 at the top 2% of the dataset (active and decoys). Finally, the model was used for screening of the filtered PubChem database to fetch molecules which can be proposed as potential PLD1 inhibitors for blocking influenza infection.

脂质代谢在流感病毒的复制及其后续感染进程中发挥着关键作用。截至目前，学界尚未完全阐明调控脂质代谢与病毒复制的具体机制，但已有研究证实，病毒感染会激活磷脂酶D（Phospholipase D，PLD1与PLD2）的两种亚型活性。体外实验（In vitro）表明，对PLD1进行化学抑制可延缓病毒入侵并降低病毒载量。本研究基于35种已报道的PLD1抑制剂，构建了三维药效团模型：研究选取其中25种化合物作为训练集，剩余10种作为测试集。本次研究共生成112个药效团模型，其中具备6个特征的AADDHR.57药效团模型，其生存评分为2.69，所构建的三维定量构效关系模型具有统计学显著性，内部训练集决定系数r²=0.97，内部测试集r²=0.71，交叉验证系数Q²=0.64。该药效团模型的预测能力通过外部测试集得到验证，外部测试集r²=0.73；同时采用系统性虚拟筛选流程进行验证，在数据集前2%的活性分子与诱饵分子中，富集因子达23.68。最后，本研究利用该模型对过滤后的PubChem数据库进行虚拟筛选，获取可作为潜在PLD1抑制剂、用于阻断流感感染的候选化合物。