Identification of anti-pathogenic activity among in silico predicted small-molecule inhibitors of Pseudomonas aeruginosa LasR or nitric oxide reductase (NOR).

IF 2 Q3 PHARMACOLOGY & PHARMACY
Drug Target Insights Pub Date : 2023-09-28 eCollection Date: 2023-01-01 DOI:10.33393/dti.2023.2638
Gemini Gajera, Niel Henriksen, Bryan Cox, Vijay Kothari
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引用次数: 0

Abstract

Introduction: Antibiotic-resistant Pseudomonas aeruginosa strains cause considerable morbidity and mortality globally. Identification of novel targets in this notorious pathogen is urgently warranted to facilitate discovery of new anti-pathogenic agents against it. This study attempted to identify small-molecule inhibitors of two important proteins LasR and nitric oxide reductase (NOR) in P. aeruginosa. 'Las' system can be said to be the 'master' regulator of quorum sensing in P. aeruginosa, whose receptor protein is LasR. Similarly, NOR is crucial to detoxification of reactive nitrogen species.

Methods: In silico identification of potential LasR or NOR inhibitors was attempted through a virtual screening platform AtomNet® to obtain a final subset of <100 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 the 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.

Results: 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.

Conclusion: Further investigation on molecular mode of action of compounds found active in this study is warranted. Virtual screening can be said to be a useful tool in narrowing down the list of compounds requiring actual wet-lab screening, saving considerable time and efforts for drug discovery.

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在硅预测的铜绿假单胞菌LasR或一氧化氮还原酶(NOR)小分子抑制剂中鉴定抗致病活性。
引言:抗抗生素铜绿假单胞菌菌株在全球范围内造成相当大的发病率和死亡率。迫切需要在这种臭名昭著的病原体中鉴定新的靶标,以促进发现新的抗病原体。这项研究试图在铜绿假单胞菌中鉴定两种重要蛋白质LasR和一氧化氮还原酶(NOR)的小分子抑制剂。”Las系统可以说是铜绿假单胞菌群体感应的“主”调节因子,其受体蛋白是LasR。同样,NOR对活性氮物种的解毒至关重要。方法:试图通过虚拟筛选平台AtomNet®对潜在的LasR或NOR抑制剂进行计算机鉴定,以通过在存在或不存在测试化合物的情况下用铜绿假单胞菌挑战模型宿主秀丽隐杆线虫来获得体内抗致病活性的最终子集。在显微镜下监测24孔测定板中蠕虫种群的存活时间达5天。结果:在96种预测的LasR抑制剂中,11种在25-50µg/mL时表现出抗假单胞菌活性(第三天终点对细菌毒力的抑制率为23%-96%)。在85种预测的NOR抑制剂中,有8种在25-50µg/mL时表现出抗假单胞菌活性(根据第二天终点,对细菌毒力的抑制率为40%-85%)。结论:有必要对本研究中发现的活性化合物的分子作用模式进行进一步研究。虚拟筛选可以说是一种有用的工具,可以缩小需要实际湿实验室筛选的化合物的范围,为药物发现节省大量时间和精力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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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