Perkasa Dian Pribadi, Darwin Darmawan, Purwanti Tri, Sanjaya Muhammad Fajar, Indryati Suci, Sugoro Irawan
Research Center for Radiation Process Technology, Research Organization for Nuclear Energy - National Research and Innovation Agency, Jakarta, Indonesia.
Research Center for Nuclear Materials and Radioactive Waste Technology, Research Organization for Nuclear Energy, National Research and Innovation Agency, Jakarta, Indonesia.
Asian Pac J Cancer Prev. 2025 Jul 1;26(7):2379-2387. doi: 10.31557/APJCP.2025.26.7.2379.
Chlorogenic acids (CGAs) are among potential natural radioprotectant for inhibiting inappropriate p53 activation of adjacent normal tissues upon radiotherapy. However, previous studies are mainly focused on 5-O-caffeoylquinic acid (5CGA). In this study, the antagonist role of three CGAs isomers against p53 protein is assed for potential anti-apoptotic activity using molecular docking and dynamic experiments.
The physicochemical and pharmacokinetic profile three CGA isomers (3-O-caffeoylquinic acid (3CGA), 4-O-caffeoylquinic acid (4CGA), and 5CGA) were predicted using SwissADME web. Subsequently, they were subjected to docking using AutoDock software against to p53's L1/S3 pocket. The best binding pose was advanced to molecular dynamic (MD) simulation spanning 5 ns to evaluate the time dependent stability using Visual Dynamic web.
The SwissADME prediction showed that the position of esterification on quinic moiety had no impact on the physicochemical and pharmacokinetic of CGA isomers. They only violated one out of five Lipinski's rules with the Abbot's bioavailability score of 0.11. The docking results revealed that the 4CGA has the highest binding energy (-5.41 kCal/mol) on L1/S3 pocket of p53 protein followed by 5CGA (-4.81 kCal/mol) and 3CGA (-4.62 kCal/mol). The MD simulation showed that the p53 complex with each CGA isomers had a root mean square deviation of less than 0.25 nm and a radius gyration that of close to reference apoprotein. Importantly, fluctuation of important residues at L1/S3 pocket was decrease through complex formation with 3CGA (at His155 and Ser121) and 4CGA (Lys120 and Ser121).
The CGA isomers satisfy the drug-likeness for a potential oral medicine. They potentially play role as anti-apoptotic agent through binding with p53's pocket that involves in DNA transcriptional activity. Among them, the 4CGA possess the highest potential due to its highest free binding affinity and its ability to stabilize the residues fluctuation in L1/S3 pocket.
绿原酸（CGAs）是潜在的天然辐射防护剂，可抑制放疗时相邻正常组织中不适当的p53激活。然而，以往的研究主要集中在5 - O - 咖啡酰奎尼酸（5CGA）上。在本研究中，使用分子对接和动力学实验评估了三种CGA异构体对p53蛋白的拮抗作用，以探讨其潜在的抗凋亡活性。
使用SwissADME网站预测三种CGA异构体（3 - O - 咖啡酰奎尼酸（3CGA）、4 - O - 咖啡酰奎尼酸（4CGA）和5CGA）的物理化学和药代动力学特征。随后，使用AutoDock软件将它们与p53的L1/S3口袋进行对接。最佳结合构象进入分子动力学（MD）模拟，时长5 ns，使用Visual Dynamic网站评估其时间依赖性稳定性。
SwissADME预测表明，奎尼酸部分的酯化位置对CGA异构体的物理化学和药代动力学没有影响。它们仅违反了五条Lipinski规则中的一条，雅培生物利用度评分为0.11。对接结果显示，4CGA在p53蛋白的L1/S3口袋上具有最高的结合能（-5.41 kCal/mol），其次是5CGA（-4.81 kCal/mol）和3CGA（-4.62 kCal/mol）。MD模拟表明，p53与每种CGA异构体形成的复合物的均方根偏差小于0.25 nm，回转半径接近参考载脂蛋白。重要的是，通过与3CGA（在His155和Ser121处）和4CGA（Lys120和Ser121处）形成复合物，L1/S3口袋处重要残基的波动减小。
CGA异构体符合潜在口服药物的类药性。它们可能通过与参与DNA转录活性的p53口袋结合而发挥抗凋亡作用。其中，4CGA由于其最高的自由结合亲和力以及稳定L1/S3口袋中残基波动的能力而具有最高的潜力。
