A Common Pharmacophore for a Diverse Set of Colchicine Site Inhibitors Using a Structure-Based Approach

Modulating the structure and function of tubulin and microtubules is an important route to
anticancer therapeutics, and therefore, small molecules that bind to tubulin and cause mitotic
arrest are of immense interest. A large number of synthetic and natural compounds with diverse
structures have been shown to bind at the colchicine site, one of the major binding sites on
tubulin, and inhibit tubulin assembly. Using the recently determined X-ray structure of the
tubulin:colchicinoid complex as the template, we employed docking studies to determine the
binding modes of a set of structurally diverse colchicine site inhibitors. These binding models
were subsequently used to construct a comprehensive, structure-based pharmacophore that
in combination with molecular dynamics simulations confirms and extends our understanding
of binding interactions at the colchicine site.

调控微管蛋白（tubulin）与微管（microtubules）的结构与功能是抗癌治疗的重要途径，因此能够结合微管蛋白并引发有丝分裂阻滞（mitotic arrest）的小分子化合物受到了广泛关注。目前已有大量结构多样的合成与天然化合物被证实可结合于微管蛋白的主要结合位点之一——秋水仙碱结合位点（colchicine site），并抑制微管蛋白组装。本研究以近期解析的微管蛋白-秋水仙碱类似物复合物的X射线晶体结构（X-ray structure）为模板，通过分子对接研究（docking studies）确定了一系列结构多样的秋水仙碱结合位点抑制剂的结合模式。随后，利用这些结合模型构建了一个全面的基于结构的药效团（structure-based pharmacophore），结合分子动力学模拟（molecular dynamics simulations）验证并拓展了我们对秋水仙碱结合位点处结合相互作用的认知。