基于mRNA翻译起始因子eIF4E结构的药物发现

Drug discovery based on the structure of the mRNA eukaryotic translation initiation factor eIF4E

关键词:  eIF4E  分子对接  序列分析  结合口袋  蛋白-药物相互作用

Key words:  eIF4E  molecular docking  sequence analysis  binding pocket  protein-drug interaction

摘要:

目的　探究mRNA翻译起始因子eIF4E的结构和作用机理，为靶向eIF4E的药物设计提供参考信息。方法 综合性阐述eIF4E家族的三维结构，运用生物信息学方法分析eIF4E家族氨基酸序列的保守性；运用DoGSiteScorer软件 预测eIF4E表面的结合口袋；运用LigPlot和PRODIGY软件，分析eIF4E与药物分子的作用模式、预测两者之间的结合自 由能；最后运用Autodock Vina软件，针对eIF4E表面结合口袋，筛选ZINC数据库FDA批准的药物分子。结果 eIF4E表 面存在 5 个潜在的药物分子结合口袋，其中结合口袋P0 体积最大，且大部分关键氨基酸都高度保守，为靶向eIF4E药物 分子的主要结合口袋。结合口袋P2 比较刚性，且氨基酸的保守性不高。P2 适用于高通量筛选靶向eIF4E的药物分子，实 验报道靶向P2 的药物分子Z5D具有很强的亲和力。研究结果发现有 5 个FDA批准的药物分子与eIF4E具有较强的结合 能力，可作为设计eIF4E抑制剂的先导化合物。结合口袋P3 主要通过疏水作用结合药物分子，且与P0 和P2 之间存在协 同效应。该协同效应表明可设计靶向eIF4E的联合用药方案。结论 eIF4E家族高度保守的氨基酸参与稳定eIF4E的三 维结构，是结合口袋的重要组成部分，严重影响eIF4E与药物分子之间的相互作用。eIF4E表面存在 5 个结合口袋，其中 P2 与药物分子Z5D具有很强的亲和力，可作为筛选药物分子的参考标准。有 5 个FDA批准的药物分子与eIF4E具有较 强结合能力。

Abstract:

Objective This work aims to study the structure and interactional mechanism of mRNA translation initiation factor eIF4E. The results may provide valuable information for the drug design targeting eIF4E. Methods Firstly, the threedimensional (3D) structure was analyzed based on the experimental structures of eIF4E family. Secondly, the conservation of the amino acids in eIF4E family are calculated based on the alignment from the bioinformatical tools. Thirdly, the DoGSiteScorer software was applied to predict the binding pocket of eIF4E. Then, the LigPlot software was used to describe the interactions between eIF4E and molecules whose binding affinity is calculated by the PRODIGY software. Finally, the drugs approved by FDA in ZINC database were fed to Autodock Vina to search molecules binding to eIF4E with high affinity. Results There are five binding pockets at the surface of eIF4E, in which the binding pocket P0 constructed by most of the highly conserved residues has the largest volume and is the main binding site of drugs targeting eIF4E. The binding pocket P2 hardly with conserved residue has the strong binding affinity with Z5D molecule. The binding pocket P2 is inflexible and is suitable for the high-throughput screening for eIF4E inhibitor. The results find there are five drugs approved by FDA with high affinity for eIF4E. These drugs can be the lead compounds for design of eIF4E inhibitor. The binding pocket P3, which has mutual effects with P0 and P2, mainly provides the hydrophobic interactions for drug binding. The mutual effects among P0, P2 and P3 suggest the feasibility of combining drugs targeting eIF4E. Conclusion The highly conserved residues play an important role in (1) the stability of the 3D structure of eIF4E , (2) the formation of the binding pockets of eIF4E, and (3) the interactions between eIF4E and molecular drugs. There are five binding pockets at the surface of eIF4E, where P2 has strong binding affinity with Z5D molecule that can function as the standard value for screening molecule binding with eIF4E. Based on P2, we showed that eIF4E has strong binding affinity with five drug molecules approved by FDA.