Structure-Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry
Structure-Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry
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DOI：
10.1002/anie.201309682
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发表时间：
2014-03-17
影响因子：
16.6
通讯作者：
Hirsch, Anna K. H.
中科院分区：
文献类型：
--
作者：
Mondal, Milon;Radeva, Nedyalka;Hirsch, Anna K. H.
基于结构的设计（SBD）可用于设计和/或优化生物靶标的新抑制剂。虽然从头SBD很少使用，但大多数关于SBD的报告都涉及初始命中的优化。动态组合化学（DCC）已成为一个强大的战略，以确定生物活性的配体，因为它使目标，以指导其最强的粘合剂的合成。我们设计了一个由五种醛和五种酰肼生成的潜在抑制剂（酰腙）库，并使用DCC来鉴定最佳结合剂。加入天冬氨酸蛋白酶内硫肽酶后，我们通过饱和转移差NMR光谱表征了蛋白结合的文库成员。共沉淀实验验证了两种最有效的抑制剂的预测结合模式，从而证明denovo SBD和DCC的组合构成了命中识别和优化的有效起点。
Structure-based design (SBD) can be used for the design and/or optimization of new inhibitors for a biological target. Whereas de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit. Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify bioactive ligands given that it enables the target to direct the synthesis of its strongest binder. We have designed a library of potential inhibitors (acylhydrazones) generated from five aldehydes and five hydrazides and used DCC to identify the best binder(s). After addition of the aspartic protease endothiapepsin, we characterized the protein-bound library member(s) by saturation-transfer difference NMR spectroscopy. Cocrystallization experiments validated the predicted binding mode of the two most potent inhibitors, thus demonstrating that the combination of denovo SBD and DCC constitutes an efficient starting point for hit identification and optimization.