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ZipA-FtsZ interaction

Jennings LD, Foreman KW, Rush TS et al (2004) Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA-FtsZ interaction. Bioorg Med Chem 12 5115-5131... [Pg.49]

Experimental screening established that compound 42 shown in Fig. 8.11 disrupts ZipA-FtsZ protein-protein interaction. However, previous studies suggested potential issues with toxicity associated with this class of compounds. Additionally such amine-substituted pyridyl-pyrimidines are heavily patented in the context of kinase inhibition. Both of these factors limit the scope of the subsequent lead optimization process, to transform this compound into a viable drug. Knowledge that compound 42 was a micromolar inhibitor of ZipA-FtsZ was exploited by searching for molecules that were similar in shape. [Pg.201]

An application of the ROCS program has been reported recently (82). New scaffolds for small molecule inhibitors of the ZipA-FtsZ protein-protein interaction have been found. The shape comparisons are made relative to the bioactive conformation of a HTS hit, determined by X-ray crystallography. A followup X-ray crystallographic analysis also showed that ROCS accurately predicted the binding mode of the inhibitor. This result offers the first experimental evidence that validates the use of ROCS for scaffold hopping purposes. [Pg.127]

Since its inception in 1996 [12], ROCS has been able to identify novel active compounds in a number of studies. The first prospective application of ROCS was intended [33] to discover new molecules that disrupt the ZipA-FtsZ protein-protein interaction, which appears to play an essential role in bacterial cell division. Using an HTS hit with JC = 12 pM as the template, a multiconformer lead-like subset of Wyeth s corporate compound collection was screened with ROCS and the three most interesting hits were reported with JQ values of73.9,83.1, and 85.1 pM, respectively. Although weaker than the original HTS hit, these molecules were smaller, did not show the same cytotoxic effects, and had less intellectual property concerns. [Pg.162]

Kenny CH, Ding W, Kelleher K et al (2003) Development of a fluorescence polarization assay to screen for inhibitors of the FtsZ/ZipA interaction. Anal Biochem 323 224—233... [Pg.49]

Somers WS, Mosyak L, Zhang Y, Glasfeld E, Haney S, Stahl M, Seehra J (2000) The bacterial cell-division protein ZipA and its interaction with an FtsZ fragment revealed by X-ray crystallography. EMBO J 19(13) 3179-3191... [Pg.90]


See other pages where ZipA-FtsZ interaction is mentioned: [Pg.16]    [Pg.77]    [Pg.16]    [Pg.77]    [Pg.201]    [Pg.434]    [Pg.156]    [Pg.166]    [Pg.321]    [Pg.17]    [Pg.18]    [Pg.328]   
See also in sourсe #XX -- [ Pg.77 ]




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