发展亲和质谱技术加速G蛋白偶联受体的配体筛选和药物发现

doi:10.3969/j.issn.0253-9608.2021.01.005

摘要/Abstract

摘要： 基于靶蛋白配体亲合作用检测的亲和质谱技术与常规高通量筛选技术相辅相成，已发展成为药物先导化合物早期发现流程中的关键技术之一。G蛋白偶联受体（GPCR）家族由于其特殊的生化性质，对基于亲合作用的配体筛选和配体表征提出了巨大的技术挑战。文章主要介绍亲和质谱技术用于GPCR配体筛选的基本原理及其特点，并总结该技术用于大规模化合物库及天然草本粗提物筛选的前沿进展。

关键词: , 亲和质谱；G蛋白偶联受体；配体筛选；药物发现

Abstract: Affinity mass spectrometry (affinity MS) based on the detection of protein target-ligand interaction is a powerful technology complementary to conventional high-throughput screening (HTS) assays and has been successfully incorporated into the early-phase lead discovery pipeline. Owing to the special biochemical properties of G protein-coupled receptors (GPCRs), tremendous technical challenges are posed to affinity MS-based ligand screening for GPCR targets. Here we briefly summarize the principle and features of the affinity MS technique adapted to GPCR ligand screening, and review the recent progress in screening both large-scale compound libraries and natural herb extracts with affinity MS for discovery of unreported GPCR ligands and modulators.

张冰洁, 水雯箐. 发展亲和质谱技术加速G蛋白偶联受体的配体筛选和药物发现[J]. 自然杂志, 2021, 43(1): 32-38.

ZHANG Bingjie, SHUI Wenqing. Developing the affinity mass spectrometry technology for the discovery of chemical ligands and drug leads towards GPCR targets[J]. Chinese Journal of Nature, 2021, 43(1): 32-38.

导出引用管理器 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

链接本文: https://www.nature.shu.edu.cn/CN/10.3969/j.issn.0253-9608.2021.01.005

https://www.nature.shu.edu.cn/CN/Y2021/V43/I1/32

[1] SANTOS R, URSU O, GAULTON A, et al. A comprehensive map of molecular drug targets [J]. Nat Rev Drug Discov, 2017, 16(1): 19-34.

[2] GOODNOW JR R A, DUMELIN C E, KEEFE A D. DNA-encoded chemistry: enabling the deeper sampling of chemical space [J]. Nat Rev Drug Discov, 2017, 16(2): 131-147.

[3] KLEINER R E, DUMELIN C ELIU D R. Small-molecule discovery from DNA-encoded chemical libraries [J]. Chem Soc Rev, 2011, 40(12): 5707-5717.

[4] KODADEK T, PACIARONI N G, BALZARINI M, et al. Beyond protein binding: Recent advances in screening DNA-encoded libraries [J]. Chem Commun (Camb), 2019, 55(89): 13330-13341.

[5] NERI D, LERNER R A. DNA-encoded chemical libraries: A selection system based on endowing organic compounds with amplifiable information [J]. Annu Rev Biochem, 2018, 87: 479-502.

[6] AHN S, KAHSAI A W, PANI B, et al. Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library [J]. Proc Natl Acad Sci USA, 2017, 114(7): 1708-1713.

[7] AHN S, PANI B, KAHSAI A W, et al. Small-molecule positive allosteric modulators of the beta2-adrenoceptor isolated from DNAencoded libraries [J]. Mol Pharmacol, 2018, 94(2): 850-861.

[8] WU Z, GRAYBILL T L, ZENG X, et al. Cell-based selection expands the utility of DNA-encoded small-molecule library technology to cell surface drug targets: Identification of novel antagonists of the NK3 tachykinin receptor [J]. ACS Comb Sci, 2015, 17(12): 722-731.

[9] ANNIS A, CHUANG C C, NAZEF N. Mass spectrometry in medicinal chemistry [M]. Weinheim, Germany: WILEY -VCH Verlag GmbH & Co KGaA, 2007: 121-156.

[10] CHEN X, LI L, CHEN S, et al. Identification of inhibitors of the antibiotic-resistance target New Delhi metallo-beta-lactamase 1 by both nanoelectrospray ionization mass spectrometry and ultrafiltration liquid chromatography/mass spectrometry approaches [J]. Anal Chem, 2013, 85(16): 7957-7965.

[11] CHEN X, QIN S, CHEN S, et al. A ligand-observed mass spectrometry approach integrated into the fragment based lead discovery pipeline [J]. Sci Rep, 2015, 5: 8361.

[12] GESMUNDO N J, SAUVAGNAT B, CURRAN P J, et al. Nanoscale synthesis and affinity ranking [J]. Nature, 2018, 557(7704): 228-232.

[13] O’CONNELL T N, RAMSAY J, RIETH S F, et al. Solution-based indirect affinity selection mass spectrometry—a general tool for high-throughput screening of pharmaceutical compound libraries [J]. Anal Chem, 2014, 86(15): 7413-7420.

[14] QIN S, REN Y, FU X, et al. Multiple ligand detection and affinity measurement by ultrafiltration and mass spectrometry analysis applied to fragment mixture screening [J]. Anal Chim Acta, 2015, 886: 98-106.

[15] KUMARI P, GHOSH E, SHUKLA A K. Emerging approaches to GPCR ligand screening for drug discovery [J]. Trends Mol Med, 2015, 21(11): 687-701.

[16] CALLERI E, CERUTI S, CRISTALLI G, et al. Frontal affinity chromatography-mass spectrometry useful for characterization of new ligands for GPR17 receptor [J]. J Med Chem, 2010, 53(9): 3489-3501.

[17] MA J, LU Y, WU D, et al. Ligand identification of the adenosine A2A receptor in self-assembled nanodiscs by affinity mass spectrometry [J]. Anal Methods, 2017, 9(40): 5851-5858.

[18] MASSINK A, HOLZHEIMER M, HOLSCHER A, et al. Mass spectrometry-based ligand binding assays on adenosine A1 and A2A receptors [J]. Purinergic Signal, 2015, 11(4): 581-594.

[19] QIN S, MENG M, YANG D, et al. High-throughput identification of G protein-coupled receptor modulators through affinity mass spectrometry screening [J]. Chem Sci, 2018, 9(12): 3192-3199.

[20] TEMPORINI C, MASSOLINI G, MARUCCI G, et al. Development of new chromatographic tools based on A2A adenosine receptor subtype for ligand characterization and screening by FAC-MS [J]. Anal Bioanal Chem, 2013, 405(2/3): 837-845.

[21] WHITEHURST C E, YAO Z, MURPHY D, et al. Application of affinity selection-mass spectrometry assays to purification and affinity-based screening of the chemokine receptor CXCR4 [J]. Comb Chem High Throughput Screen, 2012, 15(6): 473-485.

[22] YEN H Y, HOI K K, LIKO I, et al. PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling [J]. Nature, 2018, 559(7714): 423-427.

[23] YEN H Y, HOPPER J T S, LIKO I, et al. Ligand binding to a G protein-coupled receptor captured in a mass spectrometer [J]. Sci Adv, 2017, 3(6): e1701016.

[24] DENG Y, SHIPPS JR G W, COOPER A, et al. Discovery of novel, dual mechanism ERK inhibitors by affinity selection screening of an inactive kinase [J]. J Med Chem, 2014, 57(21): 8817-8826.

[25] KUTILEK V D, ANDREWS C L, RICHARDS M P, et al. Integration of affinity selection-mass spectrometry and functional cell-based assays to rapidly triage druggable target space within the NF-κB pathway [J]. J Biomol Screen, 2016, 21(6): 608-619.

[26] WALKER S S, DEGEN D, NICKBARG E, et al. Affinity selectionmass spectrometry identifies a novel antibacterial RNA polymerase inhibitor [J]. ACS Chem Biol, 2017, 12(5): 1346-1352.

[27] ZHANG T, LIU Y, YANG X, et al. Definitive metabolite identification coupled with automated ligand identification system (ALIS) technology: A novel approach to uncover structure-activity relationships and guide drug design in a factor IXa inhibitor program [J]. J Med Chem, 2016, 59(5): 1818-1829.

[28] LU Y, QIN S, ZHANG B, et al. Accelerating the throughput of affinity mass spectrometry-based ligand screening toward a G protein-coupled receptor [J]. Anal Chem, 2019, 91(13): 8162-8169.

[29] CHOI Y, JERMIHOV K, NAM S J, et al. Screening natural products for inhibitors of quinone reductase-2 using ultrafiltration LC-MS [J]. Anal Chem, 2011, 83(3): 1048-1052.

[30] FU X, WANG Z, LI L, et al. Novel chemical ligands to Ebola virus and Marburg virus nucleoproteins identified by combining affinity mass spectrometry and metabolomics approaches [J]. Sci Rep, 2016, 6: 29680.

[31] SONG H P, CHEN J, HONG J Y, et al. A strategy for screening of high-quality enzyme inhibitors from herbal medicines based on ultrafiltration LC-MS and in silico molecular docking [J]. Chem Commun (Camb), 2015, 51(8): 1494-1497.

[32] WANG L, LIU Y, LUO Y, et al. Quickly screening for potential alpha-glucosidase inhibitors from guava leaves tea by bioaffinity ultrafiltration coupled with HPLC-ESI-TOF/MS method [J]. J Agric Food Chem, 2018, 66(6): 1576-1582.

[33] WANG Z, LIANG H, CAO H, et al. Efficient ligand discovery from natural herbs by integrating virtual screening, affinity massspectrometry and targeted metabolomics [J]. Analyst, 2019, 144(9): 2881-2890.

[34] YANG Z, ZHANG Y, SUN L, et al. An ultrafiltration highperformance liquid chromatography coupled with diode array detector and mass spectrometry approach for screening and characterising tyrosinase inhibitors from mulberry leaves [J]. Anal Chim Acta, 2012, 719: 87-95.

[35] ZHANG B, ZHAO S, YANG D, et al. A Novel G protein-biased and subtype-selective agonist for a G protein-coupled receptor discovered from screening herbal extracts [J]. ACS Cent Sci, 2020, 6(2): 213-225.

[36] UDUGAMASOORIYA D G, DINEEN S P, BREKKEN R A, et al. A peptoid “antibody surrogate” that antagonizes VEGF receptor 2 activity [J]. J Am Chem Soc, 2008, 130(17): 5744-5752.

[37] HOFNER G, WANNER K T. Competitive binding assays made easy with a native marker and mass spectrometric quantification [J]. Angew Chem Int Ed Engl, 2003, 42(42): 5235-5237.

[38] NIESSEN K V, HOFNER G, WANNER K T. Competitive MS binding assays for dopamine D2 receptors employing spiperone as a native marker [J]. ChemBioChem, 2005, 6(10): 1769-1775.

[39] ZEPPERITZ C, HOFNER G, WANNER K T. MS-binding assays: kinetic, saturation, and competitive experiments based on quantitation of bound marker as exemplified by the GABA transporter mGAT1 [J]. ChemMedChem, 2006, 1(2): 208-217.

[40] NEIENS P, HOFNER G, WANNER K T. MS binding assays for D1 and D5 dopamine receptors [J]. ChemMedChem, 2015, 10(11): 1924-1931.

[41] SCHULLER M, HOFNER G, WANNER K T. Simultaneous multiple MS binding assays addressing D1 and D2 dopamine receptors [J]. ChemMedChem, 2017, 12(19): 1585-1594.

发展亲和质谱技术加速G蛋白偶联受体的配体筛选和药物发现

Developing the affinity mass spectrometry technology for the discovery of chemical ligands and drug leads towards GPCR targets

PDF

可视化

摘要/Abstract

引用本文

使用本文

相关文章 15

编辑推荐

Metrics

本文评价

[1]	向阳建, 邹何, 徐波, 魏云林. 弱毒真菌病毒在植物病害防治中的应用潜力[J]. 自然杂志, 2025, 47(5): 412-418.
[2]	姜利海, 刘培荣, 王志浩, 巫金波. 电驱动智能窗[J]. 自然杂志, 2025, 47(4): 281-288.
[3]	蒋如斌, 刘冬霞, 袁善锋, 张鸿波, 吴学珂. 雷暴电学与人工引雷[J]. 自然杂志, 2025, 47(4): 249-260.
[4]	张文霞, 俞妍, 桂可心, 周天军. 气候变化与野火[J]. 自然杂志, 2025, 47(4): 261-269.
[5]	王云鹤, 李哲涵, 邓书金, 武海斌. 基于光栅芯片的冷原子真空计量[J]. 自然杂志, 2025, 47(4): 289-293.
[6]	付勇搏, 向慧静. 癌症光疗的新纪元：发展、机制和应用[J]. 自然杂志, 2025, 47(3): 190-195.
[7]	冀婧文, 钟俊杰, 钮冰, 陈沁. 图像识别模型在野生动物保护中的应用[J]. 自然杂志, 2025, 47(3): 207-214.
[8]	钱丽嘉, 沈博宇, 郑雨轩, 蒋怿越, 陶鹏杰, 吕东潮. RNA治疗的应用及挑战[J]. 自然杂志, 2025, 47(3): 233-238.
[9]	夏丽丽, 吴陈瑶, 冯炜, 陈雨. 生物催化材料：泛催化精准医疗的“工具箱”[J]. 自然杂志, 2025, 47(3): 183-189.
[10]	赵葛剑, 张新鹏. DeepSeek：从“概率生成”到“因果推理”[J]. 自然杂志, 2025, 47(2): 79-84.
[11]	王邓, 韩健, 郭俊锋, 强亚琴. 寒武纪大爆发期间蜕皮动物躯体构型起源与演化[J]. 自然杂志, 2025, 47(2): 125-133.
[12]	张志飞, 胡亚洲, 梁悦, 刘璠, 罗梅, 张彩彬, 王棹. 寒武纪大爆发组织拼图假说与地球后生动物门类起源[J]. 自然杂志, 2025, 47(2): 95-115.
[13]	郭晓强, 李岩异. RNA研发简史：从微不足道到无比重要[J]. 自然杂志, 2022, 44(6): 480-490.
[14]	赵飞燕, 吴宇轩. 胎儿血红蛋白再生治疗β-血红蛋白病[J]. 自然杂志, 2022, 44(5): 389-397.
[15]	何韫荃, 郭阶雨, 魏香香, 孟丹. 转录因子BACH1的研究进展[J]. 自然杂志, 2022, 44(2): 79-86.