CPe-III-S Metabolism in Vitro and in Vivo and Molecular Simulation of Its Metabolites Using a p53-R273H Mutant
CPe-III-S Metabolism in Vitro and in Vivo and Molecular Simulation of Its Metabolites Using a p53-R273H Mutant
复制标题
CPe-III-S 体外和体内代谢及其使用 p53-R273H 突变体的代谢物的分子模拟
DOI：
10.1021/acs.jafc.6b01996
复制
发表时间：
2016
影响因子：
6.1
通讯作者：
Kou Xiaohong
中科院分区：
文献类型：
--
作者：
Xue Zhaohui;Wen Haichao;Wang Cen;Zhai Lijuan;Cheng Aiqing;Kou Xiaohong
先前发现，根据鹰嘴豆肽CPe-III（RQSHFANAQP）合成的CPe-III-S表现出抗增殖作用。本研究旨在探讨CPe-III-S抗肿瘤细胞增殖的作用机制。在模拟胃肠道消化环境和动物实验中，用胃蛋白酶和胰蛋白酶处理CPe-III-S。经HPLC-ESI-MS分析，鉴定出了Ser-His、His-Phe和Ala-Asn-Ala-Gln三个肽段。Ser-His是体外和体内环境中唯一常见的产物。通过分子对接实现了三种肽与p53-R273 H的特异性结合，并通过Ser-His与p53-R273 H之间的分子动力学模拟揭示了结合复合物的稳定性。配合物的结合自由能为−12.56 ± 1.03 kcal/mol，配体与p53的Thr 284之间存在可靠的氢键。Ser-His可以恢复突变型p53-R273 H活性或抑制其与下游信号的结合。该代谢物是抑制细胞增殖的潜在抗癌因子。
It was previously found that CPe-III-S, synthesized according to the chickpea peptide CPe-III (RQSHFANAQP), exhibited an antiproliferative effect. The aim of this study was to investigate the antiproliferative mechanism of CPe-III-S. CPe-III-S was treated by pepsin and trypsin in a simulated gastrointestinal digestion environment as well as in an animal experiment. With HPLC-ESI-MS analysis, three peptide fragments of Ser-His, His-Phe, and Ala-Asn-Ala-Gln were identified. Ser-His was the only common product from both in vitro and in vivo environments. The specific bindings between three peptides and p53-R273H were performed by molecular docking, and the molecular dynamic simulation between Ser-His and p53-R273H revealed the stability of the binding complex. The binding free energy of the complex was −12.56 ± 1.03 kcal/mol with a reliable hydrogen bond between the ligand and Thr284 of p53. Ser-His may restore mutant p53-R273H activity or inhibit its binding with a downstream signal. This metabolite is a potential anticancer factor for suppressing cell proliferation.