Abstract

Leishmaniasis is one of the most neglected tropical diseases that demand immediate attention to the identification of new drug targets and effective drug candidates. The present study demonstrates the possibility of using threonine synthase (TS) as a putative drug target in leishmaniasis disease management. We report the construction of an effective homology model of the enzyme that appears to be structurally as well as functionally well conserved. The 200 nanosecond molecular dynamics data on TS with and without pyridoxal phosphate (PLP) shed light on mechanistic details of PLP-induced conformational changes. Moreover, we address some important structural and dynamic interactions in the PLP binding region of TS that are in good agreement with previously speculated crystallographic estimations. Additionally, after screening more than 44,000 compounds, we propose 10 putative inhibitor candidates for TS based on virtual screening data and refined Molecular Mechanics Generalized Born Surface Area calculations. We expect that structural and functional dynamics data disclosed in this study will help initiate experimental endeavors toward establishing TS as an effective antileishmanial drug target.

Graphic abstract

中文翻译：

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建模和模拟研究，以确定苏氨酸合酶作为利什曼原虫的可能药物靶点。

摘要

利什曼病是最被忽视的热带疾病之一，需要立即关注新药靶点和有效候选药物的鉴定。本研究证明了在利什曼病管理中使用苏氨酸合酶 (TS) 作为推定的药物靶点的可能性。我们报告了一种酶的有效同源模型的构建，该模型在结构上和功能上都非常保守。具有和不具有磷酸吡哆醛 (PLP) 的 TS 的 200 纳秒分子动力学数据揭示了 PLP 诱导的构象变化的机制细节。此外，我们解决了 TS 的 PLP 结合区域中一些重要的结构和动态相互作用，这些相互作用与先前推测的晶体学估计非常一致。此外，在筛选超过 44 个之后，000 种化合物，我们基于虚拟筛选数据和改进的分子力学广义玻恩表面积计算提出了 10 种推定的 TS 抑制剂候选物。我们预计本研究中披露的结构和功能动力学数据将有助于启动实验努力，将 TS 确立为有效的抗寄生虫药物靶点。

图形摘要