在本研究中，我们对大量美国食品与药品监督管理局批准的化合物进行了筛选，以寻找靶向寄生虫的柠檬酸合酶酶的新型抗利什曼病分子。根据它们的对接和分子动力学模拟统计数据，选择了五个化合物。这些化合物符合Lipinski的五法则。此外，还进行了体外的抗利什曼病和细胞毒性研究。其中，Abemaciclib，Bazedoxifene和Vorapaxar这三个化合物显示出了有效的抗利什曼病活性，对Leishmania donovani的原虫有强烈的抗利什曼病活性，IC50值分别为0.92±0.02、0.65±0.09和6.1±0.91，对巨噬细胞内的病原体有强大的活性，EC50值分别为1.52±0.37、2.11±0.38和10.4±1.27，同时对巨噬细胞没有明显的伤害。其中，Abemaciclib根据其较低的结合能，良好的抗利什曼病活性以及与人类柠檬酸合酶的结合能存在显著差异等优点，被选为进一步使用流式细胞术和DNA断裂试验来研究死亡机制的候选化合物。此化合物的作用导致了活性氧的产生增加，线粒体膜电位的去极化，DNA损伤以及sub-G1细胞群的增加。这些特性是细胞凋亡的标志，通过凋亡测定进一步得到了证实。基于以上结果，这种抗癌化合物Abemaciclib在进一步确认后可能成为利什曼病的潜在治疗选择。© 2023 Wiley Periodicals LLC.

In this study, we have screened a large number of Food and Drug Administration-approved compounds for novel anti-leishmanial molecules targeting the citrate synthase enzyme of the parasite. Based on their docking and molecular dynamic simulation statistics, five compounds were selected. These compounds followed Lipinski's rule of five. Additionally, in vitro, antileishmanial and cytotoxicity studies were performed. The three compounds, Abemaciclib, Bazedoxifene, and Vorapaxar, had shown effective anti-leishmanial activities with IC50 values of 0.92 ± 0.02, 0.65 ± 0.09, and 6.1 ± 0.91 against Leishmania donovani promastigote and with EC50 values of 1.52 ± 0.37, 2.11 ± 0.38, 10.4 ± 1.27 against intramacrophagic amastigote without significantly harming macrophage cells. Among them, from in silico and antileishmanial activities studies, Abemaciclib had been selected based on their less binding energy, good antileishmanial activities, and also a significant difference in their binding energy with human citrate synthase for cell death mechanistic studies using flow cytometry and a DNA fragmentation assay. The action of this compound resulted in an increased reactive oxygen species production, depolarization of mitochondrial membrane potential, DNA damage, and an increase in the sub-G1 cell population. These properties are the hallmarks of apoptosis which were further confirmed by apoptotic assay. Based on the above result, this anticancer compound Abemaciclib could be employed as a potential treatment option for leishmaniasis after further confirmation.© 2023 Wiley Periodicals LLC.