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通过分子动力学模拟,虚拟选和生物试验评估,发现AI-2定数感应抑制剂,针对LSRK/HPr蛋白与蛋白相互作用部位

Yijie Xu^1,2, Chunlan Zeng², Huiqi Wen³

¹National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.

Pharmaceuticals (Basel, Switzerland)

|May 27, 2023

概括

研究人员发现了新型化合物,可以抑制LsrK和HPr蛋白之间的相互作用,这对细菌通信至关重要 (AI-2 QS). 这一发现为开发抗生素提供了新的策略,通过准细菌信号通路来开发抗生素.

科学领域:

微生物学微生物学
生物化学生物化学
药物发现药物发现药物发现

背景情况:

定数感应 (QS) 是一种细菌细胞对细胞通信系统,调节毒性和抗生素耐药性.
AI-2 QS 促进了物种间的交流,并通过 HPr 和 LsrK 蛋白与蛋白相互作用 (PPI) 与转移酶系统 (PTS) 联系在一起.

研究的目的:

发现新的AI-2 QS抑制剂 (QSI),以LsrK/HPr PPI位点为目标.
评估已识别的QSI的有效性和约束性特征.

主要方法:

用分子动力学 (MD) 模拟和虚拟选来识别潜在的QSI.
在体外测试包括基于LsrK的测试,AI-2 QS干扰测试和表面等离子体共振 (SPR) 用于评估.
进行了结构-活动关系 (SAR) 分析.

主要成果:

在62种测试的化合物中,有8种在LsrK和AI-2 QS测试中显示出显著的抑制作用.
化合物4171-0375在LSRK/HPr PPI位点 (KD = 2.51 × 10−5 M) 特别与LSRK-N蛋白结合.
SAR分析强调了疏水相互作用和键/盐桥对抑制剂有效性的重要性.

结论:

发现了针对LsrK/HPr PPI的新型AI-2 QSI,其中化合物4171-0375显示出有前途的特定结合.
这些发现为开发新的抗菌剂提供了基础,通过破坏细菌通信通路来开发新的抗菌剂.

关键词:

在AI-2中,AI-2是AI-2.在HPr的基础上,HPr 这就是LsrKK.抗菌剂是一种抗菌剂.分子动力学分子动力学议员数量检测是指对议员数量进行检测.多数感应抑制剂的可决性感应抑制剂虚拟选虚拟选虚拟选

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