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A ligand-observed mass spectrometry approach integrated into the fragment based lead discovery pipeline.


ABSTRACT: 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.

SUBMITTER: Chen X 

PROVIDER: S-EPMC4322365 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A ligand-observed mass spectrometry approach integrated into the fragment based lead discovery pipeline.

Chen Xin X   Qin Shanshan S   Chen Shuai S   Li Jinlong J   Li Lixin L   Wang Zhongling Z   Wang Quan Q   Lin Jianping J   Yang Cheng C   Shui Wenqing W  

Scientific reports 20150210


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  ...[more]

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