Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity
Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity
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DOI：
10.1016/j.bmc.2007.11.076
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发表时间：
2008-03-01
影响因子：
3.5
通讯作者：
Mooberry, Susan L.
中科院分区：
文献类型：
--
作者：
Tripathi, Ashutosh;Fornabaio, Micaela;Mooberry, Susan L.
结合在微管蛋白秋水仙碱位点的化合物引起了人们的广泛关注，研究表明这些药物可以抑制微管动力学并抑制微管蛋白聚合。报道了 18 种多取代吡咯化合物的数据，包括对人 MDA-MB-435 细胞的抗增殖活性以及将化合物对接至 αβ-微管蛋白模型后计算的结合自由能。这些对接计算与 HINT 相互作用分析相结合，能够表示抑制剂的复杂结构和结合模式，从而计算和测量的结合自由能与 0.76 的 r(2) 相关。结合袋的结构分析确定了介导结合的重要分子间接触。实验表明，与 JG-03-14（3,5-二溴-4-(3,4-二甲氧基苯基）-1H-吡咯-2-甲酸乙酯）的配合物是最稳定的。这些结果阐明了结合过程，并且对于设计新型基于吡咯的秋水仙碱位点抑制剂具有重要价值，因为这些化合物的合成非常容易。 (C) 2007 Elsevier Ltd. 保留所有权利。
Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for 18 polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 cells and calculated free energies of binding following docking the compounds into models of alpha beta-tubulin. These docking calculations coupled with HINT interaction analyses are able to represent the complex structures and the binding modes of inhibitors such that calculated and measured free energies of binding correlate with an r(2) of 0.76. Structural analysis of the binding pocket identifies important intermolecular contacts that mediate binding. As seen experimentally, the complex with JG-03-14 (3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester) is the most stable. These results illuminate the binding process and should be valuable in the design of new pyrrole-based colchicine site inhibitors as these compounds have very accessible syntheses. (C) 2007 Elsevier Ltd. All rights reserved.