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【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175–275μg/m L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。
【OBJECTIVE】 To develop a lead compound with high affinity and new structure with Pseudomonas aeruginosa mucobin synthase PBP3. 【Method】 Pseudomonas aeruginosa mucopeptide synthase PBP3 was used as a target to conduct a large-scale virtual screening of a database of 1.04 million small molecule compounds by molecular docking software DOCK6.5. The relatively simple structure-selecting compound The compounds were synthesized and their antibacterial activities were tested. 【Results】 The first round of screening was carried out by grid score. Sixty thousand compounds with grid score less than -30 kcal / mol were screened, followed by amber score for the second round of screening. The score of amber score was less than -20 About 200 kcal / mol of compound. Finally, after the observation and analysis, four kinds of high molecular weight compounds with novel structures were selected as lead compounds. The minimum inhibitory concentrations (MICs) of lead compounds and their derivatives against common microorganisms such as Pseudomonas aeruginosa were between 175-275 μg / m L, both of which were effective against Gram-negative bacteria and positive bacteria. The MIC value Lower than sulfadiazine as a positive control, indicating that the lead compound has good antibacterial activity. 【Conclusion】 These lead compounds can be further developed into new antibacterial drugs to solve the problem of drug resistance of Pseudomonas aeruginosa.