合成、计算机模拟和基于体外实验评价含恶二唑和吲哚嗪结构化合物的抗利什曼原虫活性：针对抗靶标化合物。
Synthesis, In Silico, and In Vitro Evaluation of Anti-Leishmanial Activity of Oxadiazoles and Indolizine Containing Compounds Flagged against Anti-Targets.
机构信息
Laboratory for Bioinformatics and Computational Chemistry, Institute of Nuclear Sciences VINCA, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia.
ITAV, Université de Toulouse, CNRS, 31062 Toulouse, France.
出版信息
Molecules. 2019 Apr 2;24(7):1282. doi: 10.3390/molecules24071282.
Due to the lack of approved vaccines against human leishmaniasis and the limitations of the current chemotherapy inducing side effects and drug resistance, development of new, effective chemotherapeutic agents is essential. This study describes the synthesis of a series of novel oxadiazoles and indolizine-containing compounds. The compounds were screened in silico using an EIIP/AQVN filter followed by ligand-based virtual screening and molecular docking to parasite arginase. Top hits were further screened versus human arginase and finally against an anti-target battery to tag their possible interactions with proteins essential for the metabolism and clearance of many substances. Eight candidate compounds were selected for further experimental testing. The results show measurable in vitro anti-leishmanial activity for three compounds. One compound with an IC value of 2.18 µM on intramacrophage amastigotes is clearly better positioned than the others as an interesting molecular template for further development of new anti-leishmanial agents.
由于缺乏针对人类利什曼病的批准疫苗，以及当前化疗引起副作用和耐药性的限制，开发新的、有效的化学治疗药物至关重要。本研究描述了一系列新型噁二唑和吲哚嗪类化合物的合成。使用 EIIP/AQVN 过滤器对化合物进行了计算机筛选，然后进行基于配体的虚拟筛选和分子对接，以检测寄生虫精氨酸酶。对顶级命中化合物进行了进一步的筛选，以检测其对人精氨酸酶的活性，最后对一个反靶标库进行筛选，以确定它们与蛋白质的可能相互作用，这些蛋白质对许多物质的代谢和清除至关重要。选择了 8 种候选化合物进行进一步的实验测试。结果表明，三种化合物具有可测量的体外抗利什曼原虫活性。一种化合物对巨噬细胞内无鞭毛体的 IC 值为 2.18 µM，明显优于其他化合物，是进一步开发新型抗利什曼原虫药物的有趣分子模板。
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