Integration of ligand and structure-based virtual screening for the identification of the first dual targeting agent for heat shock protein 90 (Hsp90) and tubulin.
Integration of ligand and structure-based virtual screening for the identification of the first dual targeting agent for heat shock protein 90 (Hsp90) and tubulin.
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DOI：
10.1021/jm801569z
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发表时间：
2009-04
影响因子：
7.3
通讯作者：
Andrew J. S. Knox;Trevor Price;M. Pawlak;Georgia Golfis;Christopher T Flood;D. Fayne;D. Williams;M. Meegan;David Lloyd
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文献类型：
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作者：
Andrew J. S. Knox;Trevor Price;M. Pawlak;Georgia Golfis;Christopher T Flood;D. Fayne;D. Williams;M. Meegan;David Lloyd
我们描述了一种新型吲唑基支架的发现，它代表了“一流”的双 Hsp90/微管蛋白结合化合物。两个靶标的单个已知配体共享相似的 3',4',5'-三甲氧基苯基核心，据此推测，应用集成配体和基于结构的虚拟筛选 (VS) 工作流程可以产生具有双重结合亲和力的单一支架。在验证 VS 方案后，我们成功鉴定了一种新型双重抑制剂，该抑制剂源自 160 000 种化合物的商业筛选集合。
We describe the discovery of a novel indazole-based scaffold that represents the "first-in-class" dual Hsp90/tubulin binding compound. Individual known ligands for both targets shared similar 3',4',5'-trimethoxyphenyl cores, and from this it was hypothesized that application of an integrated ligand and structure-based virtual screening (VS) workflow could yield a single scaffold with dual binding affinity. Following validation of the VS protocol, we successfully identified a novel dual inhibitor, sourced from a commercial screening collection of 160 000 compounds.