School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
Chem Biol Drug Des. 2023 Sep;102(3):444-456. doi: 10.1111/cbdd.14189. Epub 2022 Dec 15.
The natural products plinabulin, docetaxel, and vinblastine are microtubule targeting agents (MTAs). They have been used alone or in combination in cancer treatment. However, the exact nature of their effects on microtubule (MT) polymerization dynamics is poorly understood. To elucidate the longitudinal conformational and energetic changes during MT dynamics, a total of 140 ns molecular dynamic simulations combined with binding free energy calculations were performed on seven tubulin models. The results indicated that the drugs disrupted MT polymerization by altering both MT conformation and binding free energy of the neighboring tubulin subunits. The combination of plinabulin and docetaxel destabilized MT polymerization due to bending MT and weakening the polarity of tubulin polymerization. The new combination of docetaxel and vinblastine synergistically enhanced MT depolymerization and bending, while plinabulin and vinblastine had no synergistic inhibitory effects. The results were verified by the tubulin assembly assay. Our study obtained a comprehensive understanding of the action mechanisms of three natural drugs and their combinations on MT dynamic, provided theoretical guidance for new MTA combinations, and would promote the optimal use of MTA and contribute to developing new MTAs as anticancer agents.
天然产物普林司他、多西他赛和长春碱是微管靶向剂（MTAs）。它们已被单独或联合用于癌症治疗。然而，它们对微管（MT）聚合动力学的确切影响仍知之甚少。为了阐明 MT 动力学过程中的纵向构象和能量变化，对 7 个微管蛋白模型进行了总计 140ns 的分子动力学模拟，并结合结合自由能计算。结果表明，这些药物通过改变微管构象和邻近微管蛋白亚基的结合自由能来破坏 MT 聚合。普林司他和多西他赛的组合由于弯曲 MT 和削弱微管聚合的极性而使 MT 聚合不稳定。多西他赛和长春碱的新组合协同增强了 MT 解聚和弯曲，而普林司他和长春碱没有协同抑制作用。这些结果通过微管组装实验得到了验证。我们的研究全面了解了三种天然药物及其组合对 MT 动态的作用机制，为新的 MTA 组合提供了理论指导，并将促进 MTA 的最佳使用，为开发新的 MTAs 作为抗癌药物做出贡献。
