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来自Bacillus subtilis的c-di-AMP合成酶CdaA的晶体碎片屏幕

Tim Garbers¹, Piotr Neumann¹, Jan Wollenhaupt²

¹Department of Molecular Structural Biology, Institute of Microbiology and Genetics, GZMB, Georg-August-University Göttingen, Justus-von-Liebig-Weg 11, 37073 Göttingen, Germany.

Acta crystallographica. Section F, Structural biology communications

|August 23, 2024

概括

基于碎片的药物设计,针对细菌CdaA确定了保存的结合点. 诺福维尔被确定为CdaA的潜在抑制剂,为抗生素开发提供了一条新的途径.

科学领域:

结构生物学是结构生物学.
药品化学药品化学是一个
发现抗微生物药物发现.

背景情况:

结晶学断片查是针对细菌点的基于结构的药物设计的关键.
酶CdaA对于致病性细菌的循环二-AMP (c-di-AMP) 合成至关重要,是有前途的抗生素标.

研究的目的:

通过对CdaA酶进行晶体学碎片选来识别新型抗菌化合物.
探索潜在的药物重用机会,针对CdaA的保护区域.

主要方法:

纯化和结晶的CdaA酶从Streptococcus肺炎菌,细菌细菌,和菌.
基于高分辨率的X射线晶体学对96种化合物的碎片选,以对抗B. subtilis CdaA.
在 silico 药物重用屏幕中,使用已识别的碎片坐标和DrugBank 数据库.
异热定位热量计 (ITC) 证实抑制潜力.

主要成果:

B. subtilis CdaA 的结晶和衍射到 1.1 Å 的分辨率.
从碎片选中识别了8个结合位点的24个结构性命中.
发现了与保存区域结合的四个碎片,包括活性部位和二元化接口.
在基选中,特诺福维尔被确定为潜在的CdaA抑制剂,由ITC证实.

结论:

基于碎片的查是一种可行的策略,用于发现针对CdaA的抗菌剂.
诺福维尔显示出对致病性E. faecium CdaA的抑制潜力,验证了药物重用方法.
这些发现为开发针对细菌CdaA的新型抗生素的优化提供了基础.

关键词:

在CdaAA中使用.循环的二-AMP可以.停靠的对接方式碎片选碎片选碎片选碎片选新型抗生素新型抗生素

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