融合肽TP5-RGDR与神经纤毛蛋白1对接的结构模拟和优化

Structural Modeling and Optimization of the Fusion Peptide TP5-RGDR with Neuropilin-1

胸腺五肽(TP5)是一种由5个氨基酸组成的抗肿瘤多肽(序列RKDVY),可以促进胸腺成熟,调节免疫,常用于癌症的辅助治疗。有研究表明C端存在R/KXXR/K结构的多肽可以与神经纤毛蛋白1(NRP1)识别和结合而具有肿瘤归巢和细胞内化特性,能够增强药物递送。为了增强TP5的肿瘤靶向性,增强抗肿瘤效果,本实验设计了TP5-RGDR融合肽,通过计算机模拟TP5-RGDR与神经纤毛蛋白1(NRP1)结合的情况,使用MOE软件分析发现C端增加了RGDR能够增强药物的靶向性,预测了其与NRP1结合的情况,并阐明了该肽段与受体相互作用的具体信息。TP5-RGDR的R9与NRP1的D48和K79形成氢键,R6与E76形成氢键,RGDR部分与受体活性区域产生广泛连接,使配体药物牢牢连接到NRP1。并且,作者构建的83种位点突变的对接结果显示,TP5-KGDR与NRP1同样具有广泛的相互作用,但是键能会在一定程度上降低;将R9替换为K9会大幅降低末端残基的活性;D8替换为E8是可以考虑的方向,TP5-RGER也满足C端规则,但对接整体打分降低;7号位的甘氨酸明显不适宜更改。本实验通过计算机模拟的方法,成功对接了TP5-RGDR和NRP1,预测到RGDR能够促进TP5深入到细胞内部,渗透到肿瘤组织内部。在分子水平探索了TP5-RGDR的增强肿瘤靶向的机理,所有这些结果为新型抗肿瘤药物的设计提供理论依据。

Thymopentin(TP5)is an anti-cancer polypeptide(sequence RKDVY)consisting of 5 amino acids,which can promote thymus maturation,regulate immunity,and is often used in adjuvant therapy for cancer.Studies have shown that polypeptides with R/KXXR/K structure at the C-terminal can enhance drug delivery by recognizing and binding to Neuropilin-1(NRP-1)to have tumor homing and cell internalization properties.In this experiment,the fusion peptide named TP5-RGDR,which simulated the binding of TP5-RGDR to Neuropilin-1(NRP1),was designed to enhance the tumor targeting of TP5 and the anti-cancer effect.Through MOE software,the authors found that RGDR bound to the C-terminal of TP5 can improve drug targeting,and also predicted the binding of TP5-RGDR to NRP1,and elucidated the interaction of the peptide with the receptor.R9 of TP5-RGDR forms two hydrogen bonds with D48 and K79 of NRP1,R6 forms a hydrogen bond with E76,and the RGDR part is widely connected with the active region of the receptor,so that the ligand drug is firmly connected to NRP1.Moreover,the docking results of the 83 site mutations constructed by the authors showed that TP5-KGDR also had a wide range of interactions with NRP1,but the bond energy would decrease to some extent.Replacing R9 with K9 would substantially reduce the activity of the terminal residue.Replacing D8 with E8 was worth considering,and TP5-RGER also met the C-terminal rule,but the docking compound scored lower.Substitution for glycine at position 7 is clearly inappropriate.In this experiment,the authors successfully docked TP5-RGDR and NRP1 by computer simulation,and predicted that RGDR can promote TP5 to penetrate into the cells and infiltrate into the tumor tissue.The mechanism of the enhanced tumor targeting of TP5-RGDR was explored at the molecular level,and all these results provided a theoretical basis for the design of novel anti-cancer drugs.