靶向铜绿假单胞菌(Pseudomonas aeruginosa)粘肽合成酶PBP3的抗菌先导化合物的虚拟筛选及活性研究

Virtual screening and antibacterial activity of lead compounds targeting to penicillin-binding protein 3 (PBP3) of Pseudomonas aeruginosa

摘要:

[目的] 开发出与铜绿假单胞菌粘肽合成酶PBP3有高亲和力,具有全新结构的先导化合物。[方法] 以铜绿假单胞菌粘肽合成酶PBP3为靶点,通过分子对接软件DOCK6.5,对含有104万个小分子化合物的数据库进行了大规模虚拟筛选,选取结构相对简单的中选化合物进行合成,得到先导化合物,并验证其抑菌活性。[结果] 通过grid score进行第一轮初筛,筛选出grid score分值小于-30 kcal/mol的6万个化合物,接着以amber score进行第二轮筛选,筛出amber score分值小于-20 kcal/mol的化合物约200个。最终,经过观察分析,从中挑选出4种打分高并且结构新颖的小分子化合物作为先导化合物。合成出的先导化合物及其衍生物对铜绿假单胞菌等常见微生物的最小抑菌浓度(MIC)在175-275 μg/mL之间,对革兰氏阴性菌和阳性菌均有效,MIC值比作为阳性对照的磺胺嘧啶更低,说明先导化合物具有较好的抗菌活性。[结论] 这些先导化合物可以进一步开发为新型抗菌药物,用于解决铜绿假单胞菌的耐药性问题。

Abstract:

[Objective] This study was carried out to obtain lead compounds targeting penicillin-binding protein 3 (PBP3) of Pseudomonas aeruginosa by virtual screening. [Methods] UCSF dock 6.5 was used for the virtual screening from a database containing 1.04 million small molecules. Hit compounds with simple structures were synthesized and then evaluated for their antibacterial activities. [Results] Grid score was used for the first round of screening, and 60000 small molecules whose scores lower than -30 kcal/mol were screened out from the database. These molecules were subjected to the second round of screening using amber score. Approximately 200 hit compounds with scores lower than -20 kcal/mol were analyzed and 4 of them were selected as lead compounds and then synthesized. The minimal inhibition concentrations (MICs) of the lead compounds were between 175-275 μg/mL, which were lower than that of Sulfadiazine (500 μg/mL) significantly. Meanwhile, these compounds were effective for both Gram-negative and Gram-positive bacteria. [Conclusion] The lead compounds had potential to become new antibacterial agents for conquering the drug resistance of P. aeruginosa.