4ty9: Difference between revisions
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''' | ==An Ligand-observed Mass Spectrometry-based Approach Integrated into the Fragment Based Lead Discovery Pipeline== | ||
<StructureSection load='4ty9' size='340' side='right' caption='[[4ty9]], [[Resolution|resolution]] 2.78Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ty9]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TY9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TY9 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3B0:5-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE'>3B0</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4txf|4txf]], [[4txs|4txs]], [[4tya|4tya]], [[4tyb|4tyb]], [[4ty8|4ty8]]</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ty9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ty9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ty9 RCSB], [http://www.ebi.ac.uk/pdbsum/4ty9 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:25666181</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Chen, S]] | |||
[[Category: Chen, X]] | |||
[[Category: Lin, J]] | |||
[[Category: Qin, S]] | [[Category: Qin, S]] | ||
[[Category: Shui, W]] | [[Category: Shui, W]] | ||
[[Category: Yang, C]] | [[Category: Yang, C]] | ||
[[Category: Ns5b]] | |||
[[Category: Tranaferase-transferase inhibitor complex]] | |||
Revision as of 15:48, 6 May 2015
An Ligand-observed Mass Spectrometry-based Approach Integrated into the Fragment Based Lead Discovery PipelineAn Ligand-observed Mass Spectrometry-based Approach Integrated into the Fragment Based Lead Discovery Pipeline
Structural highlights
Publication Abstract from PubMedIn 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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