Abstract：
Visceral Leishmaniasis (VL), the second neglected tropical disease caused by various Leishmania species, presents a significant public health challenge due to limited treatment options and the absence of vaccines. The agent responsible for visceral leishmaniasis, also referred to as \"black fever\" in India, is Leishmania donovani. This study focuses on L. donovani Minichromosome maintenance 10 (LdMcm10), a crucial protein in the DNA replication machinery, as a potential therapeutic target in Leishmania therapy using in silico and in vitro approaches. We employed bioinformatics tools, molecular docking, and molecular dynamics simulations to predict potential inhibitors against the target protein. The research revealed that the target protein lacks homologues in the host, emphasizing its potential as a drug target. Ligands from the DrugBank database were screened against LdMcm10 using PyRx software. The top three compounds, namely suramin, vapreotide, and pasireotide, exhibiting the best docking scores, underwent further investigation through molecular dynamic simulation and in vitro analysis. The observed structural dynamics suggested that LdMcm10-ligand complexes maintained consistent binding throughout the 300 ns simulation period, with minimal variations in their backbone. These findings suggest that these three compounds hold promise as potential lead compounds for developing new drugs against leishmaniasis. In vitro experiments also demonstrated a dose-dependent reduction in L. donovani viability for suramin, vapreotide, and pasireotide, with computed IC50 values providing quantitative metrics of their anti-leishmanial efficacy. The research offers a comprehensive understanding of LdMcm10 as a drug target and provides a foundation for further investigations and clinical exploration, ultimately advancing drug discovery strategies for leishmaniasis treatment.
摘要：
内脏利什曼病（VL），由各种利什曼原虫物种引起的第二种被忽视的热带病，由于治疗选择有限和缺乏疫苗，因此提出了重大的公共卫生挑战。负责内脏利什曼病的特工，在印度也被称为“黑热病”，是多诺瓦尼利什曼尼亚.这项研究的重点是L.donovaniMinichromosome维持10（LdMcm10），DNA复制机制中的关键蛋白质,作为利什曼原虫治疗的潜在治疗靶点，使用计算机和体外方法。我们使用了生物信息学工具，分子对接,和分子动力学模拟来预测针对靶蛋白的潜在抑制剂。研究表明，目标蛋白在宿主中缺乏同源物，强调其作为药物靶标的潜力。使用PyRx软件针对LdMcm10筛选来自DrugBank数据库的配体。前三个化合物，即苏拉明，vapreotide,和pasireotide,展现最佳对接得分，通过分子动力学模拟和体外分析进行了进一步的研究。观察到的结构动力学表明，LdMcm10-配体复合物在整个300ns模拟期间保持一致的结合，在他们的骨干最小的变化。这些发现表明，这三种化合物有望成为开发抗利什曼病新药的潜在先导化合物。体外实验还证明了苏拉明的剂量依赖性降低。vapreotide,和pasireotide,计算的IC50值提供了其抗利什曼原虫疗效的定量指标。该研究提供了对LdMcm10作为药物靶标的全面了解，并为进一步的研究和临床探索奠定了基础。最终推进利什曼病治疗的药物发现策略。
