High-throughput identification of G protein-coupled receptor modulators through affinity mass spectrometry screening.
High-throughput identification of G protein-coupled receptor modulators through affinity mass spectrometry screening.
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通过亲和质谱筛选高通量鉴定 G 蛋白偶联受体调节剂。
DOI：
10.1039/c7sc04698g
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发表时间：
2018-03-28
期刊：
影响因子：
8.4
通讯作者：
Shui W
中科院分区：
文献类型：
--
作者：
Qin S;Meng M;Yang D;Bai W;Lu Y;Peng Y;Song G;Wu Y;Zhou Q;Zhao S;Huang X;McCorvy JD;Cai X;Dai A;Roth BL;Hanson MA;Liu ZJ;Wang MW;Stevens RC;Shui W
通过亲和质谱筛选高通量鉴定G蛋白偶联受体（GPCR）调节剂
G蛋白偶联受体（GPCRs）是最大类别的细胞表面蛋白，因此构成了重要的治疗靶点家族。因此，人们投入了大量精力来鉴定能够高效且选择性地调节GPCR靶点活性的新型配体。然而，由于GPCR配体发现最常用技术存在固有局限性，迫切需要更高效且有效的配体筛选方法，尤其是用于鉴定潜在的变构调节剂。在此，我们提出一种基于亲和质谱的高通量、无标记且无偏向性的筛选方法，用于鉴定针对GPCR靶点的小分子配体。这种新方法的特点是使用表达靶点的细胞膜而非纯化蛋白进行配体筛选，能够检测针对特定GPCR的正构配体和变构配体。利用该方法对一个小型化合物库进行筛选，快速发现了一种5 - 羟色胺（5 - HT）受体拮抗剂以及四种胰高血糖素样肽 - 1（GLP - 1）受体的正向变构调节剂，这些此前均未见报道。
High-throughput identification of GPCR modulators through affinity MS screening. G protein-coupled receptors (GPCRs) represent the largest class of cell surface proteins and thus constitute an important family of therapeutic targets. Therefore, significant effort has been put towards the identification of novel ligands that can modulate the activity of a GPCR target with high efficacy and selectivity. However, due to limitations inherent to the most common techniques for GPCR ligand discovery, there is a pressing need for more efficient and effective ligand screening methods especially for the identification of potential allosteric modulators. Here we present a high-throughput, label-free and unbiased screening approach for the identification of small molecule ligands towards GPCR targets based on affinity mass spectrometry. This new approach features the usage of target-expressing cell membranes rather than purified proteins for ligand screening and allows the detection of both orthosteric and allosteric ligands targeting specific GPCRs. Screening a small compound library with this approach led to the rapid discovery of an antagonist for the 5-HT receptor and four positive allosteric modulators for GLP-1 receptor that were not previously reported.
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影响因子：
--
作者：
Kutilek, Victoria D.;Andrews, Christine L.;Beutel, Bruce
通讯作者：
Beutel, Bruce
集成到基于片段的先导化合物发现流程中的配体观察质谱方法
影响因子：
4.6
作者：
Chen X;Qin S;Chen S;Li J;Li L;Wang Z;Wang Q;Lin J;Yang C;Shui W
通讯作者：
Shui W
DOI：
10.1007/978-1-61779-126-0_11
发表时间：
2011-01-01
期刊：
RECEPTOR SIGNAL TRANSDUCTION PROTOCOLS, THIRD EDITION
影响因子：
--
作者：
Briddon, Stephen J.;Kellam, Barrie;Hill, Stephen J.
通讯作者：
Hill, Stephen J.
影响因子：
7.4
作者：
Chen, Xin;Li, Lixin;Shui, Wenqing
通讯作者：
Shui, Wenqing
DOI：
10.1038/nrd.2016.230
发表时间：
2017-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Santos R;Ursu O;Gaulton A;Bento AP;Donadi RS;Bologa CG;Karlsson A;Al-Lazikani B;Hersey A;Oprea TI;Overington JP
通讯作者：
Overington JP