Dysidiolide:  A Novel Protein Phosphatase Inhibitor from the Caribbean Sponge <i>Dysidea etheria </i>de Laubenfels

Gunasekera, Sarath P.; McCarthy, Peter J.; Kelly‐Borges, Michelle; and, Emil Lobkovsky; Clardy, Jon

doi:10.1021/ja961961+

Cited by 190 publications

(138 citation statements)

References 10 publications

(16 reference statements)

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“…Of the 147 compounds investigated, 42 qualified as hits in the Cdc25A assay. The most potent compound (1) had an IC 50 value of 350 nM, which is significantly lower than the reported (50) IC 50 Thus, the hit rates for the enzymes identified as being similar to Cdc25A are Ϸ2-3%, which is a very acceptable value for an initial screen aimed exclusively at identifying hit classes. The results for the most relevant compounds are given in Table 1.…”

Section: Supporting Materials and Methods)mentioning

confidence: 83%

Compound library development guided by protein structure similarity clustering and natural product structure

Koch

Wittenberg

Basu

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

196

128

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To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound library development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11␤-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2-3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.combinatorial chemistry ͉ enzyme inhibition ͉ bioinformatics ͉ chemical biology ͉ ligand-sensing core

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Section: Supporting Materials and Methods)mentioning

confidence: 83%

Compound library development guided by protein structure similarity clustering and natural product structure

Koch

Wittenberg

Basu

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

196

128

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show abstract

“…In this series Cdc25A inhibition seemed to depend on the presence of a long aliphatic side chain and not on the sulfate moiety, which could be readily replaced with malonate without any appreciable loss in activity (Cebula et al, 1997). Another marine sponge product, dysidiolide, was initially found to inhibit Cdc25A activity in vitro (Gunsakera et al, 1996) although subsequent de novo synthesis and reanalysis indicated that pure dysidiolide either has much less or no Cdc25 inhibitory activity . Presumably the anti-Cdc25 activity found in the original dysidiolide preparation was an unidenti®ed contaminant in the extract.…”

Section: Small Molecule Inhibitors Of Cdc25mentioning

confidence: 92%

Small molecule inhibitors of dual specificity protein phosphatases

et al. 2000

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“…This concept was proven by a recent study with the natural product dysidiolide. Dysidiolide [71] targets the Cdc25A phosphatase that is involved in cell cycle regulation and represents a promising target for the development of novel anti-cancer agents [72 -74]. A protein structure similarity analysis revealed that similar ligand binding sites are found in acetylcholine esterase (AChE) with a root mean square deviation (RMSD) of the aligned C a traces of 2.74 over 49 residues and a sequence identity of 8.2 % [75].…”

Section: Kaiser Et Almentioning

confidence: 99%