铜绿假单胞菌LasR或一氧化氮还原酶(NOR)的计算机预测小分子抑制剂的抗病原活性鉴定

IF 2 Q3 PHARMACOLOGY & PHARMACY
G. Gajera, N. Henriksen, Bryan Cox, V. Kothari
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引用次数: 0

摘要

耐抗生素铜绿假单胞菌菌株引起相当大的发病率和死亡率。鉴定这种臭名昭著的病原体的新靶点是迫切需要的,以促进发现新的抗致病性药物作用于它。攻击非必要目标被认为是一种潜在的抗毒策略。本研究试图鉴定铜绿假单胞菌中两种重要蛋白LasR和一氧化氮还原酶(NOR)的小分子抑制剂。这种细菌病原体具有多个群体感应(QS)系统来调节其许多基因的表达,包括与毒力相关的基因。在这些QS系统中,“Las”系统可以说是“主”调节器,其受体蛋白为LasR。同样,NOR在活性氮解毒中起着至关重要的作用。本研究试图通过使用AtomNet®(一种专有的深度学习神经网络)的虚拟屏幕,在计算机上识别潜在的LasR或NOR抑制剂。在对大量化合物的LasR或NOR亲和力进行虚拟筛选后,通过聚类和过滤得分最高的化合物,创建了<100个化合物的最终子集。在存在或不存在测试化合物的情况下,通过用铜绿假单胞菌攻击模型宿主秀丽隐杆线虫来评估这些化合物的体内抗致病活性。在显微镜下监测24孔实验板中虫群的存活,为期5天。在96个预测的LasR抑制剂中,有11个在25-50µg/ml时表现出抗假单胞菌活性(按第三天终点,23-96%的细菌毒力抑制)。在85个预测的NOR抑制剂中,8个在25-50µg/ml时表现出抗假单胞菌活性(每第二天终点40-85%的细菌毒力抑制)。活性化合物的分子作用方式有待进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of anti-pathogenic activity among in silico predicted small-molecule inhibitors of Pseudomonas aeruginosa LasR or nitric oxide reductase (NOR)
Antibiotic resistant Pseudomonas aeruginosa strains cause considerable morbidity and mortality. Identification of novel targets in this notorious pathogen is urgently warranted to facilitate discovery of new anti-pathogenic agents acting against it. Attacking non-essential targets is believed to be a potential anti-virulence strategy. This study attempted to identify small molecule inhibitors of two important proteins LasR and nitric oxide reductase (NOR) in P. aeruginosa. This bacterial pathogen possesses multiple quorum sensing (QS) systems to regulate expression of many of its genes including those associated with virulence. Among these QS systems, ‘Las’ system can be said to be the ‘master’ regulator, whose receptor protein is LasR. Similarly, NOR plays crucial role in detoxification of reactive nitrogen species. This study attempted in silico identification of potential LasR or NOR inhibitors through a virtual screen employing AtomNet®, a proprietary deep learning neural network. Following virtual screening of a large number of compounds for their affinity to LasR or NOR, a final subset of <100 compounds was created by clustering and filtering the top scoring compounds. These compounds were evaluated for their in vivo anti-pathogenic activity by challenging the model host Caenorhabditis elegans with P. aeruginosa in presence or absence of test compounds. Survival of the worm population in 24-well assay plates was monitored over a period of 5 days microscopically. Of the 96 predicted LasR inhibitors, 11 exhibited anti-Pseudomonas activity (23-96% inhibition of bacterial virulence as per third-day end point) at 25-50 µg/ml. Of the 85 predicted NOR inhibitors, 8 exhibited anti-Pseudomonas activity (40-85% inhibition of bacterial virulence as per second-day end point) at 25-50 µg/ml. Further investigation on molecular mode of action of active compounds is warranted.
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来源期刊
Drug Target Insights
Drug Target Insights PHARMACOLOGY & PHARMACY-
CiteScore
2.70
自引率
0.00%
发文量
5
审稿时长
8 weeks
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