药物分子与靶蛋白相互作用的研究进展

李安; 周小青; 孙阔; 杨谨如; 朱勇飞; 陆一鸣

doi:10.3969/j.issn.1006-0111.2019.01.001

药物分子与靶蛋白相互作用的研究进展

doi: 10.3969/j.issn.1006-0111.2019.01.001

1.
海军军医大学药学院, 上海 200433
2.
湖南师范大学医学院, 湖南长沙 410013

基金项目: 国家自然科学基金（81773627）；国家重点研发计划（2018YFC0310900）；上海市科委"科技创新行动计划"生物医药领域科技支撑项目（16431904400）

Research advance on the interaction of pharmaceutical molecules with target proteins

1.
School of Pharmacy, Naval Medical University, Shanghai 200433, China
2.
School of Medicine, Hunan Normal University, Changsha 410013, China

摘要: 药物发挥作用是以药物分子与其靶标的相互作用为基础的，对药物-靶点相互作用的定性分析与定量检测贯穿于从新药筛选发现到走向临床的整个过程。经过几十年的发展，研究药物分子与靶蛋白间相互作用的手段已经从传统的生化实验方法转变为以先进的分子生物学、生物物理学理论为支撑的高效、准确、多样化的技术体系。笔者从靶点发现与验证、亲和力测定、相互作用位点与结构分析几个方面对代表性的方法和技术进行介绍，以期为药物研发与机制探索提供参考。
- 相互作用 /
- 靶蛋白 /
- 药物筛选 /
- 亲和力 /
- 结合位点
Abstract: The function of drugs is based on the interaction between drug molecules and their targets.Qualitative analysis and quantitative detection of drug-target interactions run through the whole process from drug discovery to clinical practice.After decades of development, the study methods on the interaction between drug molecules and target proteins have been transformed from traditional biochemical experiments to a diversity of efficient and accurate technology systems supported by advanced molecular biology and biophysics theory.In this review, representative methods and techniques were introduced from aspects of target discovery and validation, affinity determination, interaction sites and structural analysis, which might provide some references for drug discovery and mechanism exploration.
- interaction /
- target protein /
- drug screening /
- affinity /
- binding sites

[1]	MARTINEZ MOLINA D,JAFARI R,IGNATUSHCHENKO M,et al.Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay[J].Science,2013,341(6141):84-87.
[2]	SHAW J,LEVERIDGE M,NORLING C,et al.Determining direct binders of the androgen receptor using a high-throughput cellular thermal shift assay[J].Sci Rep,2018,8(1):163.
[3]	ROUX K J,KIM D I,BURKE B,et al.BioID:a screen for protein-protein interactions[J].Curr Protoc in Protein Sci,2018,91:1-15.
[4]	ZHUANG M,GUAN S,WANG H,et al.Substrates of IAP ubiquitin ligases identified with a designed orthogonal E3 ligase,the NEDDylator[J].Mol Cell,2013,49(2):273-282.
[5]	HILL Z B,POLLOCK S B,ZHUANG M,et al.Direct proximity tagging of small molecule protein targets using an engineered NEDD8 ligase[J].J Am Chem Soc,2016,138(40):13123-13126.
[6]	LINKUVIENÉ V,TALIBOV V O,DANIELSON U H,et al.Introduction of intrinsic kinetics of protein-ligand interactions and their implications for drug design[J].J Med Chem,2018,61(6):2292-2302.
[7]	POLONSCHⅡ C,DAVID S,GáSPáR S,et al.Complementarity of EIS and SPR to reveal specific and nonspecific binding when interrogating a model bioaffinity sensor; perspective offered by plasmonic based EIS[J].Anal Chem,2014,86(17):8553-8562.
[8]	HALPERN A R,WOOD J B,WANG Y,et al.Single-nanoparticle near-infrared surface plasmon resonance microscopy for real-time measurements of DNA hybridization adsorption[J].ACS Nano,2013,8(1):1022-1030.
[9]	WANG S,SHAN X,PATEL U,et al.Label-free imaging,detection,and mass measurement of single viruses by surface plasmon resonance[J].Proc Natl Acad Sci USA,2010,107(37):16028-16032.
[10]	SYAL K,WANG W,SHAN X,et al.Plasmonic imaging of protein interactions with single bacterial cells[J].Biosens Bioelectron,2015,63:131-137.
[11]	WELSCH M E,KAPLAN A,CHAMBERS J M,et al.Multivalent small-molecule pan-RAS inhibitors[J].Cell,2017,168(5):878-889.e29.
[12]	DI TRANI J M,DE CESCO S,O'LEARY R,et al.Rapid measurement of inhibitor binding kinetics by isothermal titration calorimetry[J].Nat Commun,2018,9(1):893.
[13]	WIENKEN C J,BAASKE P,ROTHBAUER U,et al.Protein-binding assays in biological liquids using microscale thermophoresis[J].Nat Commun,2010,1(7):100.
[14]	PARKER J L,NEWSTEAD S.Molecular basis of nitrate uptake by the plant nitrate transporter NRT1.1[J].Nature,2014,507(7490):68-72.
[15]	SEIDEL S A,DIJKMAN P M,LEA W A,et al.Microscale thermophoresis quantifies biomolecular interactions under previously challenging conditions[J].Methods,2013,59(3):301-315.
[16]	JERABEK-WILLEMSEN M,WIENKEN C J,BRAUN D,et al.Molecular interaction studies using microscale thermophoresis[J].Assay Drug Dev Technol,2011,9(4):342-353.
[17]	WANG J,LI H,HAN Z,et al.Allosteric receptor activation by the plant peptide hormone phytosulfokine[J].Nature,2015,525(7568):265-268.
[18]	SCHIEBEL J, RADEVA N, KÖSTER H,et al.One question,multiple answers:Biochemical and biophysical screening methods retrieve deviating fragment hit lists[J].ChemMedChem,2015,10(9):1511-1521.
[19]	BLUNDELL T L,PATEL S.High-throughput X-ray crystallography for drug discovery[J].Curr Opin Pharmacol,2004,4(5):490-496.
[20]	HUBBARD R E,MURRAY J B.Experiences in fragment-based lead discovery[J].Meth Enzymol,2011,493:509-531.
[21]	CALA O,GUILLIERE F,KRIMM I.NMR-based analysis of protein-ligand interactions[J].Anal Bioanal Chem,2014,406:943-956.
[22]	PELLECCHIA M,BERTINI I,COWBURN D,et al.Perspectives on NMR in drug discovery:a technique comes of age[J].Nat Rev Drug Discov,2008,7:738-745.
[23]	HARNER M J,FRANK A O,FESIK S W.Fragment-based drug discovery using NMR spectroscopy[J].J Biomol NMR,2013,56:65-75.
[24]	WU B,BARILE E,DE S K,et al.High-throughput screening by nuclear magnetic resonance (HTS by NMR) for the identification of PPIs antagonists[J].Curr Top Med Chem,2015,15:2032-2042.
[25]	VESTERGAARD B,SAYERS Z.Investigating increasingly complex macromolecular systems with small-angle X-ray scattering[J].IUCrJ,2014,1(Pt 6):523-529.
[26]	TUUKKANEN A T,SVERGUN D I.Weak protein-ligand interactions studied by small-angle X-ray scattering[J].FEBS J,2014,281(8):1974-1987.
[27]	NAGATOISHI S,YAMAGUCHI S,KATOH E,et al.A combination of 19F NMR and surface plasmon resonance for site-specific hit selection and validation of fragment molecules that bind to the ATP-binding site of a kinase[J].Bioorg Med Chem,2018,26(8):1929-1938.
[28]	YAN C,LIU D,LI L,et al.Discovery and characterization of small molecules that target the GTPase Ral[J].Nature,2014,515(7527):443-447.
[29]	RENAUD J P,CHUNG C W,DANIELSON U H,et al.Biophysics in drug discovery:impact,challenges and opportunities[J].Nat Rev Drug Discov,2016,15(10):679-698.

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药物分子与靶蛋白相互作用的研究进展

doi: 10.3969/j.issn.1006-0111.2019.01.001

Research advance on the interaction of pharmaceutical molecules with target proteins

计量

药物分子与靶蛋白相互作用的研究进展

doi: 10.3969/j.issn.1006-0111.2019.01.001

1. 海军军医大学药学院, 上海 200433

2. 湖南师范大学医学院, 湖南长沙 410013

English Abstract

Research advance on the interaction of pharmaceutical molecules with target proteins

1. School of Pharmacy, Naval Medical University, Shanghai 200433, China

2. School of Medicine, Hunan Normal University, Changsha 410013, China

全文HTML

目录

留言板

药物分子与靶蛋白相互作用的研究进展

doi: 10.3969/j.issn.1006-0111.2019.01.001

Research advance on the interaction of pharmaceutical molecules with target proteins

计量

出版历程

药物分子与靶蛋白相互作用的研究进展

doi: 10.3969/j.issn.1006-0111.2019.01.001

1. 海军军医大学药学院, 上海 200433 2. 湖南师范大学医学院, 湖南 长沙 410013

English Abstract

Research advance on the interaction of pharmaceutical molecules with target proteins

1. School of Pharmacy, Naval Medical University, Shanghai 200433, China 2. School of Medicine, Hunan Normal University, Changsha 410013, China

全文HTML

目录

1. 海军军医大学药学院, 上海 200433

2. 湖南师范大学医学院, 湖南长沙 410013

1. School of Pharmacy, Naval Medical University, Shanghai 200433, China

2. School of Medicine, Hunan Normal University, Changsha 410013, China