基于吡咯的抗微管蛋白剂：预测秋水仙碱位点的C-2类似物存在两种不同的结合模式。
Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.
作者信息
Da Chenxiao, Telang Nakul, Barelli Peter, Jia Xin, Gupton John T, Mooberry Susan L, Kellogg Glen E
机构信息
Department of Medicinal Chemistry & Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, USA 23298-0540.
出版信息
ACS Med Chem Lett. 2012 Jan 12;3(1):53-57. doi: 10.1021/ml200217u. Epub 2011 Nov 1.
Abstract
3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogs were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structural-activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design.
摘要
3,5-二溴-4-(3,4-二甲氧基苯基)-1H-吡咯-2-羧酸乙酯是一种有前景的抗微管蛋白先导药物，其作用靶点为微管蛋白的秋水仙碱结合位点。合成了C-2类似物并测试其微管解聚和抗增殖活性。使用GOLD对接和HINT（亲水性相互作用）评分进行的分子模拟研究揭示了两种不同的结合模式，这两种模式解释了构效关系，并与秋水仙碱与微管蛋白结合的结构基础一致。高活性化合物的结合模式在该位点中埋藏更深，并且与秋水仙碱的A环和C环很好地重叠，而低活性结合模式与微管蛋白的关键接触较少。该模型区分了高活性化合物和低活性化合物，并为秋水仙碱结合位点和化合物设计提供了新的见解。
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