Target-Based Design of Promysalin Analogues Identifies a New Putative Binding Cleft in Succinate Dehydrogenase
Target-Based Design of Promysalin Analogues Identifies a New Putative Binding Cleft in Succinate Dehydrogenase
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DOI：
10.1021/acsinfecdis.0c00024
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发表时间：
2020-06-12
影响因子：
5.3
通讯作者：
Wuest, William M.
中科院分区：
文献类型：
--
作者：
Post, Savannah J.;Keohane, Colleen E.;Wuest, William M.
普罗迈萨林是一种小分子天然产物，特异性抑制革兰氏阴性病原体铜绿假单胞菌（PA）的生长。这种活性有望用于治疗慢性疾病（如囊性纤维化）免疫功能低下患者中发现的多药耐药感染。2015年，我们的实验室完成了第一个全合成;随后的类似物设计和SAR研究使琥珀酸脱氢酶（Sdh）成为PA中的生物靶标。在此，我们报告了具有不同烷基链的新型promysalin类似物的靶向设计，其中之一与我们迄今为止最有效的类似物相当。计算对接显示，一些类似物在Sdh结合口袋中具有不同的取向，将末端碳靠近色氨酸残基。这启发了设计带有末端苯基部分的延伸侧链类似物，为未来类似物的设计提供了基础。
Promysalin is a small-molecule natural product that specifically inhibits growth of the Gram-negative pathogen Pseudomonas aeruginosa (PA). This activity holds promise in the treatment of multidrug resistant infections found in immunocom-promised patients with chronic illnesses, such as cystic fibrosis. In 2015, our lab completed the first total synthesis; subsequent analogue design and SAR investigation enabled identification of succinate dehydrogenase (Sdh) as the biological target in PA. Herein, we report the target-guided design of new promysalin analogues with varying alkyl chains, one of which is on par with our most potent analogue to date. Computational docking revealed that some analogues have a different orientation in the Sdh binding pocket, placing the terminal carbon proximal to a tryptophan residue. This inspired the design of an extended side chain analogue bearing a terminal phenyl moiety, providing a basis for the design of future analogues.