High-throughput screening identifies novel chemical scaffolds targeting Leishmania donovani parasites.

IF 4 3区 生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Diksha Kumari, Vishwani Jamwal, Tashi Palmo, Anuj Kumar, Kuljit Singh
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Abstract

High-throughput screening (HTS) is one of the critical strategies that can accelerate the process of drug discovery by exploring small drug-like molecule libraries. HTS noticeably contributes to the identification of potential hits using various automation tools and biological assays. Leishmaniasis, a neglected tropical disease, is one of the most deadly protozoan parasitic infections causing significant global burden in certain poverty-stricken countries. Given the paucity of effective chemotherapeutic agents available for the treatment of this life-threatening infection, the discovery of novel leishmanicidal scaffolds through innovative strategies is pivotal to combating this parasitic disease. In the present study, we have employed the HTS strategy to scrutinize 10,000 drug-like molecules from the in-house ChemDiv library to identify potent hits against Leishmania donovani. Noticeably, 99 molecules showed > 80% inhibitory effect against the L. donovani parasites at 50 µM concentration, and among them, four molecules displayed a 50% inhibitory concentration (IC50) value < 10 µM along with a favorable selectivity index (> 10). Scanning electron microscopy analysis suggests that these potent hits cause considerable morphological alterations. The predicted ADME or pharmacokinetics study of these potent hit molecules indicates that all the hits have considerable drug-likeness properties and showed a low risk of adverse effects, along with a predicted high level of oral bioavailability. Thus, these promising hits identified by the HTS strategy can serve as an initial basis for consequent medicinal chemistry endeavors aimed at unraveling a new series of anti-leishmanial agents.

高通量筛选鉴定针对多诺瓦利什曼原虫寄生虫的新型化学支架。
高通量筛选(HTS)是通过探索类药物小分子文库来加速药物发现过程的关键策略之一。使用各种自动化工具和生物分析,HTS明显有助于识别潜在的命中。利什曼病是一种被忽视的热带病,是最致命的原生动物寄生虫感染之一,在某些贫困国家造成重大的全球负担。鉴于缺乏有效的化疗药物可用于治疗这种危及生命的感染,通过创新策略发现新的利什曼尼支架对于对抗这种寄生虫病至关重要。在目前的研究中,我们采用HTS策略仔细检查了来自内部ChemDiv文库的10,000种药物样分子,以确定对抗多诺瓦利什曼原虫的有效命中。值得注意的是,在50µM浓度下,99个分子对L. donovani寄生虫的抑制效果为80 ~ 80%,其中4个分子的抑制浓度为50% (IC50)值10)。扫描电子显微镜分析表明,这些强效撞击引起相当大的形态改变。预测的ADME或这些强效命中分子的药代动力学研究表明,所有命中具有相当大的药物相似特性,显示出低风险的不良反应,以及预测的高水平的口服生物利用度。因此,HTS策略确定的这些有希望的命中点可以作为后续药物化学努力的初步基础,旨在揭示一系列新的抗利什曼药物。
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来源期刊
World journal of microbiology & biotechnology
World journal of microbiology & biotechnology 工程技术-生物工程与应用微生物
CiteScore
6.30
自引率
2.40%
发文量
257
审稿时长
2.5 months
期刊介绍: World Journal of Microbiology and Biotechnology publishes research papers and review articles on all aspects of Microbiology and Microbial Biotechnology. Since its foundation, the Journal has provided a forum for research work directed toward finding microbiological and biotechnological solutions to global problems. As many of these problems, including crop productivity, public health and waste management, have major impacts in the developing world, the Journal especially reports on advances for and from developing regions. Some topics are not within the scope of the Journal. Please do not submit your manuscript if it falls into one of the following categories: · Virology · Simple isolation of microbes from local sources · Simple descriptions of an environment or reports on a procedure · Veterinary, agricultural and clinical topics in which the main focus is not on a microorganism · Data reporting on host response to microbes · Optimization of a procedure · Description of the biological effects of not fully identified compounds or undefined extracts of natural origin · Data on not fully purified enzymes or procedures in which they are applied All articles published in the Journal are independently refereed.
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