Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite
Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite
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DOI：
10.1021/acs.jmedchem.8b00565
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发表时间：
2018-07-12
影响因子：
7.3
通讯作者：
Reddy, D. Srinivasa
中科院分区：
文献类型：
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作者：
Das, Pronay;Babbar, Palak;Reddy, D. Srinivasa
药物效力对非对映体构型的依赖性是一个关键方面。使用一种新的一般发散合成路线的三手性中心抗疟疾天然产物cladosporin，我们建立了完整的立体异构体库（cladologs），并评估其抑制潜力使用寄生虫，酶和结构为基础的分析。我们表明，效力是通过四氢吡喃环构象，住在寄生虫赖氨酰tRNA合成酶（KRS）的核糖结合口袋中表现出来。引人注目的是，最好和最差的对映体之间的药物效力变化500倍，KRS-进化枝复合物的结构揭示了C3和C10的改变对药物效力是有害的，而C3的变化通过谷氨酸332的旋转异构体翻转来感测。鉴于抗疟疾和抗感染药物的分数包含手性中心，这项工作提供了一个新的基础，专注于抑制剂立体化学作为抗微生物药物开发的一个方面。
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral center antimalarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme-, and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency whereas changes at C3 are sensed by rotameric flipping of glutamate 332. Given that scores of antimalarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of antimicrobial drug development.