Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia.
Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia.
Molecules. 2020 May 21;25(10):2384. doi: 10.3390/molecules25102384.
Elucidation of the mechanism of action of compounds with cellular bioactivity is important for progressing compounds into future drug development. In recent years, phenotype-based drug discovery has become the dominant approach to drug discovery over target-based drug discovery, which relies on the knowledge of a specific drug target of a disease. Still, when targeting an infectious disease via a high throughput phenotypic assay it is highly advantageous to identifying the compound's cellular activity. A fraction derived from the plant sp. showed activity against at 62.5 μge/μL. A known compound, altholactone, was identified from this fraction that showed activity towards at an minimum inhibitory concentration (MIC) of 64 μM. Retrospective analysis of a target-based screen against a TB proteome panel using native mass spectrometry established that the active fraction was bound to the mycobacterial protein Rv1466 with an estimated pseudo- of 42.0 ± 6.1 µM. Our findings established Rv1466 as the potential molecular target of altholactone, which is responsible for the observed in vivo toxicity towards .
阐明具有细胞生物活性的化合物的作用机制对于将化合物推进到未来的药物开发中非常重要。近年来，基于表型的药物发现已经成为药物发现的主导方法，而基于靶点的药物发现则依赖于对疾病特定药物靶点的了解。尽管如此，当通过高通量表型测定法针对传染病进行靶向治疗时，确定化合物的细胞活性具有很大的优势。从植物 sp. 中提取的一部分显示出对 的活性，其在 62.5 μge/μL 的浓度下有效。从该部分鉴定出一种已知化合物，即 altholactone，其对 的最小抑菌浓度（MIC）为 64 μM。使用天然质谱法对针对 TB 蛋白质组面板的基于靶点的筛选进行回顾性分析，结果表明活性部分与分枝杆菌蛋白 Rv1466 结合，估计其伪亲和力为 42.0 ± 6.1 µM。我们的研究结果确定 Rv1466 为 altholactone 的潜在分子靶标，该化合物负责观察到的体内对 的毒性。
