综合减法基因组学和基于结构的方法,揭示利什曼原虫的治疗药物靶点。

IF 2.3 3区 生物学 Q3 MICROBIOLOGY
Debanjan Saha, Anupam Nath Jha
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引用次数: 0

摘要

利什曼病是由利什曼属细胞内原生动物寄生虫引起的一种复杂的病媒传播疾病。它对全球热带和亚热带地区的公共卫生构成重大挑战。随着抗药性的增加,利什曼病的管理和控制变得更具挑战性,需要采取创新方法。为了应对这一挑战,我们的研究采用了减法基因组学和基于结构的方法来确定共同的药物靶点,并在五个利什曼病种菌株中对抗抗菌药耐药性(AMR)。减法基因组学方法揭示了谷氨酸脱氢酶(GDH)是治疗利什曼病感染的一个有希望的药物靶点。这项研究考虑了在类比研究、同源组和可药性测试中观察到的既定方法。多重序列比对揭示了 GDH 中的保守序列,而系统发生树分析则为了解 GDH 在不同利什曼原虫物种中的进化起源和密切关系提供了见解。GDH 中的保守序列及其致病功能有助于深入了解 GDH 在不同利什曼原虫中的密切关系。我们的研究采用基于结构的方法,通过分子对接和 100 ns 分子动力学(MD)模拟,展示了 GDH 与三种配体--硫醇、GW5074 和六氯芬--之间的分子相互作用。与 Bithionol 相比,GW5074 表现出稳定的 RMSD 值、更紧凑的构象和更多的氢键,因此对 GDH 有明显的亲和力。MMPBSA 分析证实了 GW5074-GDH 复合物的超强结合能,强调了其作为药物开发的强效配体的潜力。这项综合分析确定了 GW5074 是抑制利什曼原虫 GDH 活性的有希望的候选药物,有助于开发针对利什曼原虫感染的有效疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Integrated subtractive genomics and structure-based approach to unravel the therapeutic drug target of Leishmania species

Integrated subtractive genomics and structure-based approach to unravel the therapeutic drug target of Leishmania species

Leishmaniasis is a complex vector-borne disease caused by intracellular protozoan parasites of the Leishmania genus. It presents a significant public health challenge in tropical and subtropical regions globally. As resistance to treatment increases, managing and controlling Leishmaniasis becomes more challenging, necessitating innovative approaches. To address this challenge, our study utilized subtractive genomics and structure-based approaches to identify common drug targets and combat antimicrobial resistance (AMR) across five Leishmania species strains. The subtractive genomics approach unraveled Glutamate Dehydrogenase (GDH) as a promising drug target for treating Leishmania infections. The investigation considered established methodologies observed in analogous studies, orthologous group, and druggability tests. Multiple sequence alignment revealed conserved sequences in GDH, while phylogenetic tree analysis provided insights into the evolutionary origin and close relationships of GDH across Leishmania species. Conserved sequences in GDH along with its function in pathogenicity provided insights into the close relationships of GDH across Leishmania species. Using a structure-based approach, our study showed the molecular interactions between GDH and three ligands—Bithionol, GW5074, and Hexachlorophene—through molecular docking and 100 ns molecular dynamics (MD) simulations. GW5074 exhibited a significant affinity for GDH, as indicated by stable RMSD values, a more compact conformation, and a higher number of hydrogen bonds than Bithionol. MMPBSA analysis confirmed the superior binding energy of the GW5074-GDH complex, emphasizing its potential as a potent ligand for drug development. This comprehensive analysis identified GW5074 as a promising candidate for inhibiting GDH activities in Leishmania species, contributing to the development of effective therapeutics against Leishmania infections.

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来源期刊
Archives of Microbiology
Archives of Microbiology 生物-微生物学
CiteScore
4.90
自引率
3.60%
发文量
601
审稿时长
3 months
期刊介绍: Research papers must make a significant and original contribution to microbiology and be of interest to a broad readership. The results of any experimental approach that meets these objectives are welcome, particularly biochemical, molecular genetic, physiological, and/or physical investigations into microbial cells and their interactions with their environments, including their eukaryotic hosts. Mini-reviews in areas of special topical interest and papers on medical microbiology, ecology and systematics, including description of novel taxa, are also published. Theoretical papers and those that report on the analysis or ''mining'' of data are acceptable in principle if new information, interpretations, or hypotheses emerge.
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