Department of Chemistry, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510182, China,
J Mol Model. 2014 Feb;20(2):2070. doi: 10.1007/s00894-014-2070-6. Epub 2014 Jan 29.
The binding mode of (-)-zampanolide (ZMP) to tubulin was investigated using docking, molecular dynamics (MD) simulation, and binding free-energy calculations. The docking studies validated the experimental results indicating that the paclitaxel site is the binding site for (-)-ZMP. The 18 ns MD simulation shows the docking mode has changed a lot, whereas it offers more reliable binding data. MM-PBSA binding free-energy calculations further confirmed the results of the MD simulation. The study revealed that hydrophobic interactions play an important role in stabilizing the binding, and the strong hydrogen bond formed with Asp224 enhances the affinity for tubulin. Meanwhile, the results support the assumption that (-)-ZMP can be attacked by His227, leading to a nucleophilic reaction and covalent binding. These theoretical results lead to a greater understanding of the mechanism of action of binding to tubulin, and will therefore aid the design of new compounds with higher affinities for tubulin.
采用对接、分子动力学（MD）模拟和结合自由能计算研究了 (-)-zampanolide（ZMP）与微管蛋白的结合模式。对接研究验证了实验结果，表明紫杉醇结合位点是 (-)-ZMP 的结合位点。18ns 的 MD 模拟表明对接模式发生了很大变化，提供了更可靠的结合数据。MM-PBSA 结合自由能计算进一步证实了 MD 模拟的结果。研究表明，疏水相互作用在稳定结合中起着重要作用，与 Asp224 形成的强氢键增强了与微管蛋白的亲和力。同时，结果支持 (-)-ZMP 可以被 His227 攻击的假设，导致亲核反应和共价结合。这些理论结果加深了对与微管蛋白结合作用机制的理解，因此有助于设计与微管蛋白具有更高亲和力的新型化合物。
