A Ligand-observed Mass Spectrometry Approach Integrated into the Fragment Based Lead Discovery Pipeline

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	A Ligand-observed Mass Spectrometry Approach Integrated into the Fragment Based Lead Discovery Pipeline
	Chen, Xin 1,2,3; Qin, Shanshan 1,2,3; Chen, Shuai 1,2,3; Li, Jinlong 1,4; Li, Lixin 2,3; Wang, Zhongling 1,2,3; Wang, Quan 1,2,3; Lin, Jianping 2,3; Yang, Cheng 2,3,4; Shui, Wenqing 1,5
刊名	SCIENTIFIC REPORTS
	2015-02-10
卷号	5
英文摘要	In fragment-based lead discovery (FBLD), a cascade combining multiple orthogonal technologies is required for reliable detection and characterization of fragment binding to the target. Given the limitations of the mainstream screening techniques, we presented a ligand-observed mass spectrometry approach to expand the toolkits and increase the flexibility of building a FBLD pipeline especially for tough targets. In this study, this approach was integrated into a FBLD program targeting the HCV RNA polymerase NS5B. Our ligand-observed mass spectrometry analysis resulted in the discovery of 10 hits from a 384-member fragment library through two independent screens of complex cocktails and a follow-up validation assay. Moreover, this MS-based approach enabled quantitative measurement of weak binding affinities of fragments which was in general consistent with SPR analysis. Five out of the ten hits were then successfully translated to X-ray structures of fragment-bound complexes to lay a foundation for structure-based inhibitor design. With distinctive strengths in terms of high capacity and speed, minimal method development, easy sample preparation, low material consumption and quantitative capability, this MS-based assay is anticipated to be a valuable addition to the repertoire of current fragment screening techniques.
WOS标题词	Science & Technology
类目[WOS]	Multidisciplinary Sciences
研究领域[WOS]	Science & Technology - Other Topics
关键词[WOS]	DEPENDENT RNA-POLYMERASE ; HEPATITIS-C VIRUS ; X-RAY CRYSTALLOGRAPHY ; DRUG DISCOVERY ; NONNUCLEOSIDE INHIBITORS ; COMBINATORIAL LIBRARIES ; DISSOCIATION-CONSTANTS ; IDENTIFICATION ; DESIGN ; ESI
收录类别	SCI
语种	英语
WOS记录号	WOS:000349172800005
内容类型	期刊论文
源URL	[http://124.16.173.210/handle/834782/1433]
专题	天津工业生物技术研究所_生物质谱与定量生物学研究水雯箐_期刊论文
作者单位	1.Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China 2.Tianjin Joint Acad Biotechnol & Med, High Throughput Mol Drug Discovery Ctr, Tianjin 300457, Peoples R China 3.Nankai Univ, State Key Lab Med Chem, Tianjin 300071, Peoples R China 4.Nankai Univ, Dept Pharm, Tianjin 300071, Peoples R China 5.Chinese Acad Sci, Tianjin Inst Ind Biotechnol, Tianjin 300308, Peoples R China
推荐引用方式 GB/T 7714	Chen, Xin,Qin, Shanshan,Chen, Shuai,et al. A Ligand-observed Mass Spectrometry Approach Integrated into the Fragment Based Lead Discovery Pipeline[J]. SCIENTIFIC REPORTS,2015,5.
APA	Chen, Xin.,Qin, Shanshan.,Chen, Shuai.,Li, Jinlong.,Li, Lixin.,...&Shui, Wenqing.(2015).A Ligand-observed Mass Spectrometry Approach Integrated into the Fragment Based Lead Discovery Pipeline.SCIENTIFIC REPORTS,5.
MLA	Chen, Xin,et al."A Ligand-observed Mass Spectrometry Approach Integrated into the Fragment Based Lead Discovery Pipeline".SCIENTIFIC REPORTS 5(2015).