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针对细菌β滑动的小分子,通过结合的in silico和in vitro选方法发现

Alessia Caputo¹, Gian Marco Elisi^2,3, Elisabetta Levati¹

¹Laboratory of Biochemistry and Molecular Biology, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.

Journal of enzyme inhibition and medicinal chemistry

|January 3, 2025

概括

抗生素耐药性是一个主要的威胁. 研究人员发现了新的小分子,通过准蛋白质-蛋白质相互作用来破坏细菌DNA复制,从而提供了潜在的新抗菌治疗方法.

科学领域:

微生物学微生物学
药物发现药物发现药物发现
分子生物学分子生物学

背景情况:

抗生素耐药性对全球健康构成重大风险,需要开发新的抗菌策略.
蛋白与蛋白相互作用 (PPI) 对微生物功能至关重要,并且代表了新药的有希望的目标.
细菌DNA聚合酶III的α子单元和β滑动之间的相互作用对DNA复制至关重要.

研究的目的:

为了确定新型的小分子,抑制细菌DNA聚合酶III全酶内的α/β互动.
发现新的化学支架,以开发有效的抗菌剂,向关键的细菌过程.

主要方法:

基于药解剂的虚拟选4000个小分子对β结合口袋.
在体外验证使用BRET测定,蛋白热转移和竞争ELISA.
对DNA聚合酶III功能的抑制活性的评估.

主要成果:

鉴定了4000种候选抑制剂,有3种已确认的结果和28种类似物.
提亚[4,5-d]-胺二和本扎尼利德衍生物显示出微分子功效.
这些化合物有效地取代了β,并抑制了DNA复制.

结论:

这项研究确定了α/β-clamp PPI破坏者的新化学类.
这些化合物抑制细菌DNA聚合酶III活性,显示抗菌药物开发的潜力.
进一步优化这些可能会提高它们的抗菌功效.

关键词:

细菌DNA聚合酶是一种细菌DNA聚合酶.抗生素抗生素是一种抗生素.蛋白蛋白相互作用抑制剂蛋白蛋白相互作用抑制剂虚拟选虚拟选虚拟选酵母酵母生物发光共振能量转移 (yBRET)

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