Use of the tubulin bound paclitaxel conformation for structure-based rational drug design
Use of the tubulin bound paclitaxel conformation for structure-based rational drug design
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DOI：
10.1016/j.chembiol.2005.01.004
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发表时间：
2005-03-01
影响因子：
--
通讯作者：
Ojima, I
中科院分区：
文献类型：
--
作者：
Geney, R;Sun, L;Ojima, I
开发了一种新的计算对接方案，并结合微管结合2-(对氟苯甲酰基)紫杉醇的Redor-核磁共振实验所获得的构象信息来描述紫杉醇独特的微管蛋白结合结构。设计并合成了一种构象受限的大环紫杉醇类化合物，它在C-14和C-3‘N位置之间带有连接物，以加强这种“红色紫杉醇”构象。新的紫杉类化合物SB-T-2053对人乳腺癌细胞MCF-7和LCC-6(野生型和耐药细胞)的生长抑制作用与紫杉醇的作用数量级相同。此外，SB-T-2053在体外诱导微管蛋白聚合至少与紫杉醇一样，这直接验证了我们的药物设计过程。这些结果为下一代紫杉类化合物和其他微管稳定剂的药物设计开辟了一条新的途径，基于药物-微管蛋白复合体的精细结构信息，符合典型的酶抑制剂药物化学规则。
A new computational docking protocol has been developed and used in combination with conformational information inferred from REDOR-NMR experiments on microtubule bound 2-(p-fluorobenzoyl)paclitaxel to delineate a unique tubulin binding structure of paclitaxel. A conformationally constrained macrocyclic taxoid bearing a linker between the C-14 and C-3'N positions has been designed and synthesized to enforce this "REDOR-taxol" conformation. The novel taxoid SB-T-2053 inhibits the growth of MCF-7 and LCC-6 human breast cancer cells (wild-type and drug resistant) on the same order of magnitude as paclitaxel. Moreover, SB-T-2053 induces in vitro tubulin polymerization at least as well as paclitaxel, which directly validates our drug design process. These results open a new avenue for drug design of next generation taxoids and other microtubule-stabilizing agents based on the refined structural information of drug-tubulin complexes, in accordance with typical enzyme-inhibitor medicinal chemistry precepts.