Centre for Metabolomics and Bioanalysis (CEMBIO) , Facultad de Farmacia, Universidad CEU San Pablo , Campus Montepríncipe, Boadilla del Monte , 28668 Madrid , Spain.
GSK I+D Diseases of the Developing World (DDW), Parque Tecnológico de Madrid , Calle de Severo Ochoa 2 , 28760 Tres Cantos, Madrid , Spain.
ACS Chem Biol. 2018 May 18;13(5):1361-1369. doi: 10.1021/acschembio.8b00204. Epub 2018 Apr 24.
A lack of viable hits, increasing resistance, and limited knowledge on mode of action is hindering drug discovery for many diseases. To optimize prioritization and accelerate the discovery process, a strategy to cluster compounds based on more than chemical structure is required. We show the power of metabolomics in comparing effects on metabolism of 28 different candidate treatments for Leishmaniasis (25 from the GSK Leishmania box, two analogues of Leishmania box series, and amphotericin B as a gold standard treatment), tested in the axenic amastigote form of Leishmania donovani. Capillary electrophoresis-mass spectrometry was applied to identify the metabolic profile of Leishmania donovani, and principal components analysis was used to cluster compounds on potential mode of action, offering a medium throughput screening approach in drug selection/prioritization. The comprehensive and sensitive nature of the data has also made detailed effects of each compound obtainable, providing a resource to assist in further mechanistic studies and prioritization of these compounds for the development of new antileishmanial drugs.
缺乏可行的命中、耐药性的增加以及对作用模式的有限了解，阻碍了许多疾病的药物发现。为了优化优先级排序并加速发现过程，需要一种基于不仅仅是化学结构的化合物聚类策略。我们展示了代谢组学在比较 28 种不同利什曼病候选治疗方法（25 种来自 GSK 利什曼虫箱，两种利什曼虫箱系列的类似物，以及两性霉素 B 作为金标准治疗）对利什曼原虫无性体的代谢影响方面的强大功能。我们应用毛细管电泳-质谱法来鉴定利什曼原虫的代谢谱，并使用主成分分析来根据潜在作用模式对化合物进行聚类，为药物选择/优先级排序提供了一种高通量筛选方法。该数据的全面和敏感性质还使得可以获得每种化合物的详细影响，为进一步的机制研究和这些化合物的开发提供了资源，用于新的抗利什曼药物。
