2v22

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{{STRUCTURE_2v22| PDB=2v22 | SCENE= }}
{{STRUCTURE_2v22| PDB=2v22 | SCENE= }}
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'''REPLACE: A STRATEGY FOR ITERATIVE DESIGN OF CYCLIN BINDING GROOVE INHIBITORS'''
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===REPLACE: A STRATEGY FOR ITERATIVE DESIGN OF CYCLIN BINDING GROOVE INHIBITORS===
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==Overview==
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We describe a drug-design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) in which nonpeptidic surrogates for specific determinants of known peptide ligands are identified in silico by using a core peptide-bound protein structure as a design anchor. In the REPLACE application example, we present the effective replacement of two critical binding motifs in a lead protein-protein interaction inhibitor pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These were identified through docking of fragment libraries into the volume of the cyclin-binding groove of CDK2/cyclin A vacated through truncation of the inhibitor peptide-binding determinants. Proof of concept for this strategy was obtained through the generation of potent peptide-small-molecule hybrids and by the confirmation of inhibitor-binding modes in X-ray crystal structures. This method therefore allows nonpeptide fragments to be identified without the requirement for a high-sensitivity binding assay and should be generally applicable in replacing amino acids as individual residues or groups in peptide inhibitors to generate pharmaceutically acceptable lead molecules.
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The line below this paragraph, {{ABSTRACT_PUBMED_17051658}}, adds the Publication Abstract to the page
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{{ABSTRACT_PUBMED_17051658}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors., Andrews MJ, Kontopidis G, McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, Fischer PM, Chembiochem. 2006 Dec;7(12):1909-15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17051658 17051658]
REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors., Andrews MJ, Kontopidis G, McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, Fischer PM, Chembiochem. 2006 Dec;7(12):1909-15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17051658 17051658]
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Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design., Kontopidis G, McInnes C, Pandalaneni SR, McNae I, Gibson D, Mezna M, Thomas M, Wood G, Wang S, Walkinshaw MD, Fischer PM, Chem Biol. 2006 Feb;13(2):201-11. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16492568 16492568]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Serine/threonine-protein kinase]]
[[Category: Serine/threonine-protein kinase]]
[[Category: Transferase]]
[[Category: Transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 18:04:24 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 02:57:26 2008''

Revision as of 23:57, 27 July 2008

Image:2v22.png

Template:STRUCTURE 2v22

REPLACE: A STRATEGY FOR ITERATIVE DESIGN OF CYCLIN BINDING GROOVE INHIBITORS

Template:ABSTRACT PUBMED 17051658

About this Structure

2V22 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors., Andrews MJ, Kontopidis G, McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, Fischer PM, Chembiochem. 2006 Dec;7(12):1909-15. PMID:17051658

Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design., Kontopidis G, McInnes C, Pandalaneni SR, McNae I, Gibson D, Mezna M, Thomas M, Wood G, Wang S, Walkinshaw MD, Fischer PM, Chem Biol. 2006 Feb;13(2):201-11. PMID:16492568

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