Organic Chemistry Division , CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road , Pune 411008 , India.
Academy of Scientific and Innovative Research (AcSIR) , New Delhi 110025 , India.
J Med Chem. 2018 Jul 12;61(13):5664-5678. doi: 10.1021/acs.jmedchem.8b00565. Epub 2018 Jun 4.
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.
药物效力对非对映异构体构型的依赖性是一个关键方面。我们使用一种新颖的三手性中心抗疟天然产物克拉多菌素的通用发散合成途径，构建了其完整的立体异构体文库（克拉多洛格），并使用寄生虫、酶和基于结构的测定法评估了它们的抑制潜力。我们表明，效力通过四氢吡喃环构象表现出来，这些构象位于寄生虫赖氨酸 tRNA 合成酶（KRS）的核糖结合口袋中。引人注目的是，最强和最差对映异构体之间的药效相差 500 倍，并且 KRS-克拉多洛格复合物的结构表明，C3 和 C10 处的改变对药效不利，而 C3 处的改变则通过谷氨酸 332 的构象翻转来感知。鉴于大量抗疟药和抗感染药物都含有手性中心，这项工作为将抑制剂立体化学作为抗菌药物开发的一个方面提供了新的基础。
