Departmento de Farmacologia, Universidad de Alcala, Madrid, Spain.
Anticancer Agents Med Chem. 2012 Mar;12(3):219-25. doi: 10.2174/187152012800228841.
The Vinca alkaloids are a group of widely used anticancer drugs, originally extracted from the Madagascar periwinkle, that disrupt microtubule dynamics in mammalian cells by interfering with proper assembly of α,β-tubulin heterodimers. They favor curved tubulin assemblies that destabilize microtubules and induce formation of spiral aggregates. Their binding energy profiles have been characterized by means of sedimentation velocity assays and the binding site of vinblastine at the interface between two tubulin dimers (α1β1 � α2β2) has been ascertained by X-ray crystallographic studies on a complex of tubulin with the stathmin-like domain of protein RB3, albeit at relatively low resolution. Here we use molecular modeling and simulation techniques to build, refine and perform a comparative analysis of the three-dimensional complexes of vinblastine, vincristine, vinorelbine and vinflunine with a β1α2-tubulin interface in explicit water to rationalize the binding affinity differences in structural and energetic terms. Our results shed some more light into the binding determinants and the structure-activity relationships of these clinically useful agents.
长春碱类是一组广泛应用的抗癌药物，最初从马达加斯加长春花中提取，通过干扰α、β-微管蛋白异二聚体的正确组装来破坏哺乳动物细胞中的微管动力学。它们有利于形成弯曲的微管组装体，从而使微管不稳定，并诱导螺旋聚集体的形成。它们的结合能谱已通过沉降速度测定法进行了表征，长春碱在微管与 RB3 蛋白的 stathmin 样结构域复合物中的结合位点（α1β1�α2β2）已通过 X 射线晶体学研究确定，尽管分辨率相对较低。在这里，我们使用分子建模和模拟技术，构建、优化和比较长春碱、长春新碱、长春瑞滨和长春氟宁与β1α2-微管蛋白界面的三维复合物，在明确的水环境中，以合理的结构和能量术语来解释结合亲和力的差异。我们的结果进一步阐明了这些临床有用药物的结合决定因素和结构-活性关系。
