Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia.
Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, 530200, China.
Mar Drugs. 2020 Mar 5;18(3):149. doi: 10.3390/md18030149.
In recent years, there has been a revival of interest in phenotypic-based drug discovery (PDD) due to target-based drug discovery (TDD) falling below expectations. Both PDD and TDD have their unique advantages and should be used as complementary methods in drug discovery. The PhenoTarget approach combines the strengths of the PDD and TDD approaches. Phenotypic screening is conducted initially to detect cellular active components and the hits are then screened against a panel of putative targets. This PhenoTarget protocol can be equally applied to pure compound libraries as well as natural product fractions. Here we described the use of the PhenoTarget approach to identify an anti-tuberculosis lead compound. Fractions from were identified with activity against H37Rv. Native magnetic resonance mass spectrometry (MRMS) against a panel of 37 proteins from proteomes showed that a fraction from a 95% ethanol re-extraction specifically formed a protein-ligand complex with Rv1466, a putative uncharacterized protein. The natural product responsible was isolated and characterized to be polycarpine. The molecular weight of the ligand bound to Rv1466, 233 Da, was half the molecular weight of polycarpine less one proton, indicating that polycarpine formed a covalent bond with Rv1466.
近年来，由于基于靶点的药物发现（TDD）未能达到预期效果，基于表型的药物发现（PDD）重新引起了人们的兴趣。PDD 和 TDD 都有其独特的优势，应该在药物发现中作为互补方法使用。PhenoTarget 方法结合了 PDD 和 TDD 方法的优势。首先进行表型筛选以检测细胞活性成分，然后针对一组假定的靶标筛选命中物。这种 PhenoTarget 方案可同样适用于纯化合物库和天然产物馏分。在这里，我们描述了使用 PhenoTarget 方法来鉴定抗结核先导化合物。从 中鉴定出对 H37Rv 具有活性的馏分。针对 37 种蛋白质的天然磁共振质谱（MRMS）显示，来自 95%乙醇再提取的馏分特异性地与 Rv1466 形成蛋白配体复合物，Rv1466 是一种假定的未鉴定蛋白质。分离并鉴定出负责的天然产物为多卡宾。与 Rv1466 结合的配体的分子量为 233 Da，是多卡宾分子量减去一个质子的一半，表明多卡宾与 Rv1466 形成了共价键。
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