亚马逊利什曼原虫n -肉豆浆酰基转移酶潜在抑制剂的研究:计算和实验研究

IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mariana Sant’Anna Pereira Nicolau, Millena Almeida Resende, Cintia de Campos Chaves, Renata Santos Rodrigues, Veridiana de Melo Rodrigues, Nilson Nicolau-Junior, Kelly Aparecida Geraldo Yoneyama
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引用次数: 0

摘要

利什曼病是一种由利什曼原虫寄生虫引起的疾病,在全球,特别是在拉丁美洲和巴西,对健康构成重大威胁。亚马逊利什曼原虫是一个重要的物种,因为它与皮肤利什曼病和非典型内脏利什曼病有关。目前的治疗受到毒性、耐药性和高成本的阻碍,推动了对新的治疗靶点和药物的需求。n -肉豆蔻酰基转移酶(NMT)是抗利什曼原虫的重要靶点。n -肉豆蔻酰基转移酶(NMT)是利什曼原虫的一个重要靶标,因为它在肉豆蔻酰基化过程中起着至关重要的作用,肉豆蔻酰基化是一种脂质修饰,涉及肉豆蔻酸盐(一种14碳饱和脂肪酸)附着到特定蛋白质的n端。在这项工作中,采用基于形状的建模方法来识别亚马逊利什曼原虫潜在的NMT抑制剂。以吡唑磺胺为参考配体,建立并验证了基于五特征形状的模型。对DIVERSet EXP和CL文库(约100万个化合物)进行虚拟筛选,根据TanimotoCombo评分对每个子集排名前500位的分子进行优先排序。分子对接研究根据ChemPLP评分和对接姿势一致性从每个子集中确定了三个排名最高的化合物。在所选择的配体中,CL 54016012、EXP 6689657和EXP 9226834表现出最有利的结合相互作用,CL 54016012与Tyr80、Tyr217和Tyr345形成稳定的氢键。分子动力学(MD)模拟表明,尽管观察到结合能和氢键的变化,但配体结合并未显著改变NMT的结构稳定性。CL 54016012的对接评分最高,RMSD稳定性最佳,IC50预测值最低(19.81 μM),提示其作为先导化合物的潜力。体外细胞毒性实验表明,CL 54016012、CL 74995016和EXP 6689657以剂量依赖的方式降低了亚马逊河蛭的活力,这使它们成为抗利什曼原虫药物开发的有希望的候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Investigation of Potential Inhibitors of N-Myristoyltransferase in Leishmania amazonensis: A Computational and Experimental Study

Investigation of Potential Inhibitors of N-Myristoyltransferase in Leishmania amazonensis: A Computational and Experimental Study

Leishmaniasis, a disease caused by Leishmania parasites, poses a significant health threat globally, particularly in Latin America and Brazil. Leishmania amazonensis is an important species because it is associated with both cutaneous leishmaniasis and an atypical visceral form. Current treatments are hindered by toxicity, resistance, and high cost, driving the need for new therapeutic targets and drugs. N-myristoyltransferase (NMT) is an important anti-leishmanial target. N-myristoyltransferase (NMT) is an important target in Leishmania parasites, as it plays a crucial role in the process of myristoylation, a lipid modification that involves the attachment of myristate, a 14-carbon saturated fatty acid, to the N-terminus of specific proteins. In this work, a shape-based modeling approach was employed to identify potential NMT inhibitors in Leishmania amazonensis. Using a pyrazole sulphonamide as a reference ligand, a five-feature shape-based model was developed and validated. Virtual screening of the DIVERSet EXP and CL libraries (~1 million compounds) prioritized the top 500 ranked molecules per subset based on the TanimotoCombo score. Molecular docking studies identified the three highest-ranking compounds from each subset based on ChemPLP scores and docking pose consistency. Among the selected ligands, CL 54016012, EXP 6689657, and EXP 9226834 exhibited the most favorable binding interactions, with CL 54016012 forming stable hydrogen bonds with Tyr80, Tyr217, and Tyr345. Molecular dynamics (MD) simulations indicated that ligand binding did not significantly alter NMT structural stability, although variations in binding energy and hydrogen bond were observed. CL 54016012 demonstrated the highest docking score, optimal RMSD stability, and the lowest predicted IC50 value (19.81 μM), suggesting its potential as a lead compound. In vitro cytotoxicity assays revealed that CL 54016012, CL 74995016, and EXP 6689657 reduced L. amazonensis viability in a dose-dependent manner, placing them as promising candidates for further investigation in anti-leishmanial drug development.

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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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