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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Rationale and design of an inhibitor of RecA protein as an inhibitor of Acinetobacter baumannii
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Rationale and design of an inhibitor of RecA protein as an inhibitor of Acinetobacter baumannii

机译：RECA蛋白抑制剂作为植物抑制剂的理由和设计

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摘要

Acinetobacter baumannii is one of the ESKAPE pathogen, which causes pneumonia, urinary tract infections, and is linked to high degree of morbidity and mortality. One-way antibiotic and disinfectant resistance is acquired by the activation of RecA-mediated DNA repair (SOS-response) that maintain ROS-dependent DNA damage caused by these anti-bacterial molecules. To increase the efficacy of different anti-microbial, there is a need to design an inhibitor against RecA of A. baumannii. We have performed homology modeling to generate the structure of RecA, followed by model refinement and validation. Highthroughput virtual screening of 1,80,313 primary and secondary metabolites against RecA was performed in HTVS, SP, and XP docking modes. The selected 195 compounds were further analyzed for binding free energy by molecular mechanics approach. The selected top two molecules from molecular mechanics approach were further validated by molecular dynamics simulation (MDS). In-silico high-throughput virtual screening and MDS validation identified ZINC01530654 or (+-)-2-((4-((7-Chloro-4-quinolyl)amino)pentyl)ethylamino)ethanol sulfate (or hydroxychloroquine sulfate) as a possible lead molecule binding to RecA protein. We have experimentally determined the mechanism of ZINC01530654 to RecA protein. These findings suggest a strategy to chemically inhibit the vital process controlled by RecA that could be helpful for the development of new antibacterial agents.
机译：鲍曼不动杆菌是ESKAPE病原体之一，可引起肺炎、尿路感染，并与高发病率和死亡率有关。通过激活RecA介导的DNA修复（SOS反应），维持这些抗菌分子引起的ROS依赖性DNA损伤，获得单向抗生素和消毒剂耐药性。为了提高不同抗菌药物的效果，有必要设计一种针对鲍曼不动杆菌RecA的抑制剂。我们进行了同源性建模以生成RecA的结构，然后进行了模型细化和验证。在HTV、SP和XP对接模式下，对1,80313种针对RecA的初级和次级代谢产物进行了高通量虚拟筛选。用分子力学方法进一步分析了所选195个化合物的结合自由能。分子动力学模拟（MDS）进一步验证了从分子力学方法中选出的前两个分子。在电子高通量虚拟筛选和MDS验证中，ZINC01530654或（+-）-2-（（4-（（7-氯-4-喹啉）氨基）戊基）乙基氨基）乙醇硫酸盐（或羟基氯喹硫酸盐）被确定为与RecA蛋白结合的可能先导分子。我们通过实验确定了ZINC01530654对RecA蛋白的作用机制。这些发现表明了一种化学抑制RecA控制的重要过程的策略，这可能有助于开发新的抗菌剂。

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