Leishmaniasis is a tropical neglected disease that imposes major health concerns in many endemic countries worldwide and requires urgent attention to the identification of new drug targets as well as drug candidates. In the current study, we propose homoserine kinase (HSK) inhibition as a strategy to induce pathogen mortality via generating threonine deficiency. We introduce a homology-based molecular model of leishmanial HSK that appears to possess all conserved structural as well as functional features in the GHMP kinase family. Furthermore, 200 ns molecular dynamics data of the enzyme in open and closed state attempts to provide the mechanistic details involved in the substrate as well as phosphate binding to this enzyme. We discuss the structural and functional significance of movements involved in various loops (motif 1, 2, 3) and lips (upper and lower) in the transition of leishmanial HSK from closed to open state. Virtual screening data of more than 40,000 compounds from the present investigation tries to identify a few potential HSK inhibitors that possess important features to act as efficient HSK inhibitors. These compounds can be considered an effective starting point for the identification of novel drug-like scaffolds. We hope the structural wealth that is offered in this report will be utilized in designing competent experimental and therapeutic interventions for leishmaniasis management.

Graphical abstract

中文翻译：

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高丝氨酸激酶作为利什曼原虫有效靶点的分子模型和模拟研究。

利什曼病是一种被忽视的热带病，在全世界许多流行国家中都引起重大健康问题，需要紧急注意确定新的药物靶标和候选药物。在当前的研究中，我们建议抑制高丝氨酸激酶（HSK）作为通过产生苏氨酸缺乏症诱导病原体死亡的策略。我们介绍了一个基于同源性的利什曼原虫HSK分子模型，该模型似乎具有GHMP激酶家族中所有保守的结构以及功能特征。此外，在打开和关闭状态下该酶的200 ns分子动力学数据试图提供涉及底物以及与该酶结合的磷酸盐的机械细节。我们讨论了涉及各种循环的运动的结构和功能意义（基序1、2，3）利什曼HSK从闭合状态向打开状态过渡时，嘴唇（上和下）。来自本研究的40,000多种化合物的虚拟筛选数据试图确定一些潜在的HSK抑制剂，这些抑制剂具有充当有效HSK抑制剂的重要特征。这些化合物可以被认为是鉴定新型药物样支架的有效起点。我们希望本报告中提供的结构性财富将用于设计用于利什曼病管理的有效实验和治疗干预措施。这些化合物可以被认为是鉴定新型药物样支架的有效起点。我们希望本报告中提供的结构性财富将用于设计用于利什曼病管理的有效实验和治疗干预措施。这些化合物可以被认为是鉴定新型药物样支架的有效起点。我们希望本报告中提供的结构性财富将用于设计用于利什曼病管理的有效实验和治疗干预措施。

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