Drug discovery from natural products using affinity selection-mass spectrometry.
Drug discovery from natural products using affinity selection-mass spectrometry.
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DOI：
10.1016/j.ddtec.2021.10.005
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
van Breemen RB
中科院分区：
文献类型：
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作者：
Muchiri RN;van Breemen RB
作为药物发现的起点，亲和选择质谱 (AS-MS) 非常适合从植物、真菌和微生物提取物等多种化学来源中发现先导化合物。基于大分子受体和低分子量配体之间的结合相互作用，AS-MS 能够从复杂的混合物中快速分离出具有药理活性的小分子，以进行质谱表征和鉴定。与传统的高通量筛选不同，AS-MS 不需要放射性标记、紫外线或荧光发色团，并且与所有类别的受体、酶、孵育缓冲液、辅因子和配体兼容。最成功的 AS-MS 类型包括脉冲超滤 (PUF) AS-MS、尺寸排阻色谱 (SEC) AS-MS 和磁微珠亲和选择筛选 (MagMASS)，它们的不同之处在于将混合物中的配体-受体复合物与非结合化合物分离的方法。亲和分离后，使用高分辨率 UHPLC-MS 和串联质谱法对混合物中的配体进行表征。基于这些元素组成和结构数据，通过搜索已知天然产物的在线数据库并与标准品进行比较来确定先导化合物的身份。新型天然产物的结构是通过结合二维核磁共振和质谱等光谱技术来确定的。
As a starting point for drug discovery, affinity selection-mass spectrometry (AS-MS) is ideal for the discovery of lead compounds from chemically diverse sources such as botanical, fungal and microbial extracts. Based on binding interactions between macromolecular receptors and ligands of low molecular mass, AS-MS enables the rapid isolation of pharmacologically active small molecules from complex mixtures for mass spectrometric characterization and identification. Unlike conventional high-throughput screening, AS-MS requires no radiolabels, no UV or fluorescent chromophores, and is compatible with all classes of receptors, enzymes, incubation buffers, cofactors, and ligands. The most successful types of AS-MS include pulsed ultrafiltration (PUF) AS-MS, size exclusion chromatography (SEC) AS-MS, and magnetic microbead affinity selection screening (MagMASS), which differ in their approaches for separating the ligand-receptor complexes from the non-binding compounds in mixtures. After affinity isolation, the ligand(s) from the mixture are characterized using high resolution UHPLC-MS and tandem mass spectrometry. Based on these elemental composition and structural data, the identities of the lead compounds are determined by searching on-line databases for known natural products and by comparison with standards. The structures of novel natural products are determined using a combination of spectroscopic techniques including two-dimensional NMR and MS.