基于 NMR 光谱的碎片药物发现。
Fragment-based drug discovery using NMR spectroscopy.
机构信息
Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave, 607 Light Hall, Nashville, TN 37232-0146, USA.
出版信息
J Biomol NMR. 2013 Jun;56(2):65-75. doi: 10.1007/s10858-013-9740-z. Epub 2013 May 18.
Abstract
Nuclear magnetic resonance (NMR) spectroscopy has evolved into a powerful tool for fragment-based drug discovery over the last two decades. While NMR has been traditionally used to elucidate the three-dimensional structures and dynamics of biomacromolecules and their interactions, it can also be a very valuable tool for the reliable identification of small molecules that bind to proteins and for hit-to-lead optimization. Here, we describe the use of NMR spectroscopy as a method for fragment-based drug discovery and how to most effectively utilize this approach for discovering novel therapeutics based on our experience.
摘要
在过去的二十年中，核磁共振（NMR）光谱已经发展成为基于片段的药物发现的有力工具。虽然 NMR 传统上用于阐明生物大分子及其相互作用的三维结构和动力学，但它也可以成为一种非常有价值的工具，可用于可靠地鉴定与蛋白质结合的小分子，以及进行命中到先导化合物的优化。在这里，我们描述了 NMR 光谱作为基于片段的药物发现方法的用途，以及如何根据我们的经验，最有效地利用这种方法来发现新的治疗药物。
相似文献
1
Fragment-based drug discovery using NMR spectroscopy.基于 NMR 光谱的碎片药物发现。
J Biomol NMR. 2013 Jun;56(2):65-75. doi: 10.1007/s10858-013-9740-z. Epub 2013 May 18.
2
NMR spectroscopy: the swiss army knife of drug discovery.NMR 光谱学：药物发现的瑞士军刀。
J Biomol NMR. 2020 Nov;74(10-11):509-519. doi: 10.1007/s10858-020-00330-0. Epub 2020 Jul 2.
3
Advancing fragment binders to lead-like compounds using ligand and protein-based NMR spectroscopy.利用基于配体和蛋白质的核磁共振光谱法将片段结合剂推进至类先导化合物。
Methods Enzymol. 2011;493:469-85. doi: 10.1016/B978-0-12-381274-2.00018-2.
4
Revisiting biomolecular NMR spectroscopy for promoting small-molecule drug discovery.重新审视生物分子 NMR 光谱学在促进小分子药物发现中的作用。
J Biomol NMR. 2020 Nov;74(10-11):501-508. doi: 10.1007/s10858-020-00314-0. Epub 2020 Apr 18.
5
NMR in structure-based drug design.基于结构的药物设计中的 NMR。
Essays Biochem. 2017 Nov 8;61(5):485-493. doi: 10.1042/EBC20170037.
6
A Practical Perspective on the Roles of Solution NMR Spectroscopy in Drug Discovery.药物发现中溶液 NMR 光谱学作用的实用观点
Molecules. 2020 Jun 28;25(13):2974. doi: 10.3390/molecules25132974.
7
Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification.基于核磁共振的片段筛选策略——靶点固定：用于片段命中识别的TINS、STD和SPR方法比较
J Biomol Screen. 2010 Sep;15(8):978-89. doi: 10.1177/1087057110375614.
8
Ligand-Orientation Based Fragment Selection in STD NMR Screening.基于配体取向的STD NMR筛选片段选择
J Med Chem. 2015 Nov 12;58(21):8739-42. doi: 10.1021/acs.jmedchem.5b01114. Epub 2015 Oct 29.
9
NMR quality control of fragment libraries for screening.用于筛选的片段文库的 NMR 质量控制。
J Biomol NMR. 2020 Nov;74(10-11):555-563. doi: 10.1007/s10858-020-00327-9. Epub 2020 Jun 12.
10
Development and Validation of 2D Difference Intensity Analysis for Chemical Library Screening by Protein-Detected NMR Spectroscopy.二维差示强度分析方法的建立与验证及其在蛋白检测 NMR 筛选化学库中的应用。
Chembiochem. 2018 Mar 2;19(5):448-458. doi: 10.1002/cbic.201700386. Epub 2018 Jan 25.
引用本文的文献
1
Combining MicroED and native mass spectrometry for structural discovery of enzyme-small molecule complexes.结合微聚焦电子衍射（MicroED）和原生质谱用于酶-小分子复合物的结构发现
Proc Natl Acad Sci U S A. 2025 Aug 5;122(31):e2503780122. doi: 10.1073/pnas.2503780122. Epub 2025 Jul 28.
2
Advancing Target Validation and Ligandability Assessment: Fragment Screening via F NMR Spectroscopy.推进靶点验证和可配体性评估：通过核磁共振光谱法进行片段筛选。
Methods Mol Biol. 2025;2905:193-206. doi: 10.1007/978-1-0716-4418-8_13.
3
Drugging Challenging Cancer Targets Using Fragment-Based Methods.利用基于片段的方法靶向治疗具有挑战性的癌症靶点。
Chem Rev. 2025 Mar 26;125(6):3586-3594. doi: 10.1021/acs.chemrev.4c00892. Epub 2025 Mar 5.
4
Perspectives on Applications of F-NMR in Fragment-Based Drug Discovery.F-核磁共振在基于片段的药物发现中的应用前景
Molecules. 2024 Dec 5;29(23):5748. doi: 10.3390/molecules29235748.
5
Probing Protein-Ligand Methyl-π Interaction Geometries through Chemical Shift Measurements of Selectively Labeled Methyl Groups.通过选择性标记甲基的化学位移测量探究蛋白质-配体甲基-π相互作用几何结构
J Med Chem. 2024 Aug 8;67(15):13187-13196. doi: 10.1021/acs.jmedchem.4c01128. Epub 2024 Jul 28.
6
A ligand discovery toolbox for the WWE domain family of human E3 ligases.一种用于人类 E3 连接酶 WWE 结构域家族的配体发现工具包。
Commun Biol. 2024 Jul 24;7(1):901. doi: 10.1038/s42003-024-06584-w.
7
Fragment-based drug discovery campaigns guided by native mass spectrometry.基于天然质谱的片段药物发现研究
RSC Med Chem. 2024 May 22;15(7):2270-2285. doi: 10.1039/d4md00273c. eCollection 2024 Jul 17.
8
Impact of structural biology and the protein data bank on us fda new drug approvals of low molecular weight antineoplastic agents 2019-2023.2019-2023 年结构生物学和蛋白质数据库对美国食品和药物管理局批准的新型低分子量抗肿瘤药物的影响。
Oncogene. 2024 Jul;43(29):2229-2243. doi: 10.1038/s41388-024-03077-2. Epub 2024 Jun 17.
9
Use of phosphotyrosine-containing peptides to target SH2 domains: Antagonist peptides of the Crk/CrkL-p130Cas axis.利用含磷酸酪氨酸的肽来靶向 SH2 结构域：Crk/CrkL-p130Cas 轴的拮抗剂肽。
Methods Enzymol. 2024;698:301-342. doi: 10.1016/bs.mie.2024.04.013. Epub 2024 Apr 27.
10
Optimizing NMR fragment-based drug screening for membrane protein targets.优化针对膜蛋白靶点的基于核磁共振片段的药物筛选
J Struct Biol X. 2024 May 25;9:100100. doi: 10.1016/j.yjsbx.2024.100100. eCollection 2024 Jun.
本文引用的文献
1
Characterization of Ligand Binding by Saturation Transfer Difference NMR Spectroscopy.通过饱和转移差核磁共振波谱法对配体结合进行表征
Angew Chem Int Ed Engl. 1999 Jun 14;38(12):1784-1788. doi: 10.1002/(SICI)1521-3773(19990614)38:12<1784::AID-ANIE1784>3.0.CO;2-Q.
2
Compound Design by Fragment-Linking.碎片连接的化合物设计。
Mol Inform. 2011 Apr 18;30(4):298-306. doi: 10.1002/minf.201000174. Epub 2011 Apr 6.
3
New approaches for NMR screening in drug discovery.药物发现中核磁共振筛选的新方法。
Drug Discov Today Technol. 2004 Dec;1(3):277-83. doi: 10.1016/j.ddtec.2004.10.003.
4
Scaffold hopping.骨架跃迁
Drug Discov Today Technol. 2004 Dec;1(3):217-24. doi: 10.1016/j.ddtec.2004.10.009.
5
HTS by NMR of combinatorial libraries: a fragment-based approach to ligand discovery.基于核磁共振的组合文库高通量筛选：一种基于片段的配体发现方法。
Chem Biol. 2013 Jan 24;20(1):19-33. doi: 10.1016/j.chembiol.2012.10.015.
6
Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors.片段生长和连接导致新型纳摩尔乳酸脱氢酶抑制剂。
J Med Chem. 2013 Feb 14;56(3):1023-40. doi: 10.1021/jm3014844. Epub 2013 Jan 9.
7
Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.利用片段基方法和基于结构的设计发现有效的髓样细胞白血病 1（Mcl-1）抑制剂。
J Med Chem. 2013 Jan 10;56(1):15-30. doi: 10.1021/jm301448p. Epub 2012 Dec 17.
8
Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation.发现与K-Ras结合并抑制Sos介导激活的小分子。
Angew Chem Int Ed Engl. 2012 Jun 18;51(25):6140-3. doi: 10.1002/anie.201201358. Epub 2012 May 8.
9
SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-x(L) and Mcl-1.基于配体间核 Overhauser 效应（ILOEs）的 SAR 研究发现了针对 Bcl-x(L) 和 Mcl-1 的酰基磺酰胺类化合物的活性。
J Med Chem. 2011 Sep 8;54(17):6000-13. doi: 10.1021/jm200826s. Epub 2011 Aug 4.
10
Fragment-based drug design: computational & experimental state of the art.基于片段的药物设计：计算与实验的最新进展
Comb Chem High Throughput Screen. 2011 Jul;14(6):500-20. doi: 10.2174/138620711795767884.
Zotero 插件