a 1 College of Chemical Science and Technology and Pharmacy, Key Laboratory of Education Ministry for Medicinal Chemistry of Natural Resource, Yunnan University , Kunming , P. R. China.
J Biomol Struct Dyn. 2019 Sep;37(15):4080-4091. doi: 10.1080/07391102.2018.1539412. Epub 2018 Nov 18.
Vinblastine (VLB) and its derivatives have been used for clinical first-line drugs to treat various cancers. Due to the resistance and serious side effects from using VLB and its derivatives, there is a need to discover and develop novel VLB derivatives with high activity against cancer cells. In order to better discover and develop new VLB derivatives, we need to study the structural basis of VLB's anti-cancer cytotoxicity and the mechanism of its interaction with α,β-tubulins. Based on the crystal structure of α,β-microtubule complex protein, the molecular dynamics method including the sampling PMF method was used to study the variation of dissociation free energy (Δ) of α,β-tubulins under different system conditions, and then from which to study the mechanism of the interaction between VLB and α,β-tubulins. The obtained results show that the dissociation of pure α,β-tubulins requires 197.8 kJ·mol for Δ. When the VLB molecule exists between the interface of α,β-tubulins, the dissociation Δ of α,β-tubulins reaches 220.5 kJ·mol, which is greater than that of pure α,β-tubulin. The VLB molecule is formed by connecting a vindoline moiety (VM) molecule with a catharanthine moiety (CM) molecule through a carbon-carbon bond, which is a larger molecule. When the CM molecule exists in the middle of α,β-tubulin interface, the dissociation Δ of α,β-tubulins is 46.2 kJ·mol, during which the CM moves with β-tubulin. When the VM molecule exists between the middle of α,β-tubulin interface, the dissociation Δ of α,β-tubulins is 86.7 kJ·mol, during which it moves with α-tubulin. Therefore, the VLB molecule is like a double-sides tape to stick α-tubulin and β-tubulin together. The VLB molecule intervenes the dynamic equilibrium between dissociation and aggregation of α-tubulin and β-tubulin by a double-sides sticking mechanism to exert high activity with toxicity against cancer cell. Besides, our results demonstrate that VLB has its structural basis for anticancer cytotoxicity due to its two compositions composed of a CM molecule and a VM molecule although they have little toxicity against cancer cell alone.
长春碱（VLB）及其衍生物已被用作治疗各种癌症的临床一线药物。由于使用 VLB 及其衍生物会产生耐药性和严重的副作用，因此需要发现和开发对癌细胞具有高活性的新型 VLB 衍生物。为了更好地发现和开发新的 VLB 衍生物，我们需要研究 VLB 抗癌细胞毒性的结构基础及其与α、β-微管蛋白相互作用的机制。基于α、β-微管蛋白复合物的晶体结构，采用分子动力学方法，包括采样 PMF 方法，研究了在不同系统条件下α、β-微管蛋白解离自由能（Δ）的变化，进而研究了 VLB 与α、β-微管蛋白相互作用的机制。研究结果表明，纯α、β-微管蛋白的解离需要 197.8 kJ·mol。当 VLB 分子存在于α、β-微管蛋白界面之间时，α、β-微管蛋白的解离Δ达到 220.5 kJ·mol，大于纯α、β-微管蛋白。VLB 分子是由一个长春质碱（VM）分子通过碳-碳键与一个长春新碱（CM）分子连接而成的，是一个较大的分子。当 CM 分子存在于α、β-微管蛋白界面中间时，α、β-微管蛋白的解离Δ为 46.2 kJ·mol，在此过程中，CM 与β-微管蛋白一起移动。当 VM 分子存在于α、β-微管蛋白界面中间时，α、β-微管蛋白的解离Δ为 86.7 kJ·mol，在此过程中，它与α-微管蛋白一起移动。因此，VLB 分子就像双面胶一样将α-微管蛋白和β-微管蛋白粘在一起。VLB 分子通过双面粘贴机制干预α-微管蛋白和β-微管蛋白的解离和聚合的动态平衡，对癌细胞发挥高毒性的高活性。此外，我们的研究结果表明，VLB 具有其抗癌细胞毒性的结构基础，因为它由一个 CM 分子和一个 VM 分子组成，尽管它们单独对癌细胞的毒性很小。
