Linked Life Data

21067198

Source:http://linkedlifedata.com/resource/pubmed/id/21067198

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pubmed-article:21067198pubmed:abstractTextProtein-protein interactions are an intricate part of biological pathways and have become important targets for drug discovery. Here we present a two-stage magnetic bead assay to functionally screen small-molecule mixtures for modulators of protein-based interactions, with simultaneous affinity-based isolation of active compounds and identification by mass spectrometry. Proteins of interest interact in solution prior to the addition of Ni(II)-functionalized magnetic beads to recover an intact protein-protein complex through affinity capture of a polyhistidine-tagged primary target ("protein-complex fishing"). Protein-complex fishing, utilizing His(6)-tagged calmodulin (CaM) as the primary (bait) protein and melittin (Mel) as the target, was used to screen a mass-encoded library of 1000 bioactive compounds (50 mixtures, 20 compounds each) and successfully identified three known antagonists, three naturally occurring phenolic compounds previously reported to disrupt CaM-activated phosphodiesterase activity, and two newly identified modulators of the CaM-Mel interaction, methylbenzethonium and pempidine tartrate. The ability to produce quantitative inhibition data is also shown through the development of dose-dependent response curves and the determination of inhibition constants (K(I)) for the novel compound methylbenzethonium (K(I) = 14-49 nM) and two known antagonists, calmidazolium (K(I) = 1.7-7.5 nM) and trifluoperazine (K(I) = 1.2-3.0 ?M), with the latter two values being in close agreement with literature values.lld:pubmed
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pubmed-article:21067198pubmed:authorpubmed-author:BrennanJohn...lld:pubmed
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pubmed-article:21067198pubmed:year2010lld:pubmed
pubmed-article:21067198pubmed:articleTitleMagnetic "fishing" assay to screen small-molecule mixtures for modulators of protein-protein interactions.lld:pubmed
pubmed-article:21067198pubmed:affiliationChemical Biology Graduate Program, Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.lld:pubmed
pubmed-article:21067198pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:21067198pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed