Nguyen Tam Luong, McGrath Connor, Hermone Ann R, Burnett James C, Zaharevitz Daniel W, Day Billy W, Wipf Peter, Hamel Ernest, Gussio Rick
Target Structure-Based Drug Discovery Group, Developmental Therapeutics Program, National Cancer Institute, Frederick, Maryland 21702, USA.
J Med Chem. 2005 Sep 22;48(19):6107-16. doi: 10.1021/jm050502t.
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.
调节微管蛋白和微管的结构与功能是抗癌治疗的重要途径，因此，与微管蛋白结合并导致有丝分裂停滞的小分子备受关注。大量结构各异的合成化合物和天然化合物已被证明可结合在秋水仙碱位点（微管蛋白上的主要结合位点之一）并抑制微管蛋白组装。以最近确定的微管蛋白：秋水仙碱类复合物的X射线结构为模板，我们采用对接研究来确定一组结构多样的秋水仙碱位点抑制剂的结合模式。这些结合模型随后被用于构建一个全面的、基于结构的药效团，该药效团与分子动力学模拟相结合，证实并扩展了我们对秋水仙碱位点结合相互作用的理解。
