4tya

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

spinqualitylabelsall models 4tya, resolution 2.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4tya is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3AE Related: 4txf, 4txs, 4ty8, 4ty9, 4tyb Activity: RNA-directed RNA polymerase, with EC number 2.7.7.48 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. A ligand-observed mass spectrometry approach integrated into the fragment based lead discovery pipeline.,Chen X, Qin S, Chen S, Li J, Li L, Wang Z, Wang Q, Lin J, Yang C, Shui W Sci Rep. 2015 Feb 10;5:8361. doi: 10.1038/srep08361. PMID:25666181 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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