Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.
Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.
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DOI：
10.1021/ml200217u
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发表时间：
2012-01-12
影响因子：
4.2
通讯作者：
Kellogg, Glen E.
中科院分区：
文献类型：
--
作者：
Da, Chenxiao;Telang, Nakul;Barelli, Peter;Jia, Xin;Gupton, John T.;Mooberry, Susan L.;Kellogg, Glen E.
关键词：
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剂，靶向微管蛋白的秋水仙碱位点。合成了 C-2 类似物并测试了微管解聚和抗增殖活性。使用 GOLD 对接和 HINT（水疗相互作用）评分的分子模型研究揭示了两种不同的结合模式，这两种模式解释了结构-活性关系，并且符合秋水仙碱与微管蛋白结合的结构基础。较高活性化合物的结合模式埋藏在该位点较深的位置，并与秋水仙碱的 A 环和 C 环很好地重叠，而较低活性的结合模式则显示与微管蛋白的关键接触较少。该模型将高活性化合物与活性较弱的化合物区分开来，并为秋水仙碱位点和化合物设计提供了新的见解。
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.
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影响因子：
13.3
作者：
Stanton, Richard A.;Gernert, Kim M.;Nettles, James H.;Aneja, Ritu
通讯作者：
Aneja, Ritu
影响因子：
5.6
作者：
JONES, G;WILLETT, P;GLEN, RC
通讯作者：
GLEN, RC
影响因子：
5.8
作者：
Arthur, Christopher R.;Gupton, John T.;Gewirtz, David A.
通讯作者：
Gewirtz, David A.
影响因子：
3.5
作者：
Tripathi, Ashutosh;Fornabaio, Micaela;Mooberry, Susan L.
通讯作者：
Mooberry, Susan L.
影响因子：
7.3
作者：
WIREKO, FC;KELLOGG, GE;ABRAHAM, DJ
通讯作者：
ABRAHAM, DJ