2v22: Difference between revisions

Revision as of 19:52, 21 February 2008

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

OverviewOverview

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.

About this StructureAbout this Structure

2V22 is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Known structural/functional Sites: and . Full crystallographic information is available from OCA.

ReferenceReference

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

Page seeded by OCA on Thu Feb 21 18:52:39 2008

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OCA

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 ==Overview==
-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.
+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.
 ==About this Structure==
-V22 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=C35:'>C35</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Known structural/functional Sites: <scene name='pdbsite=AC1:C35 Binding Site For Residue B 1433'>AC1</scene> and <scene name='pdbsite=AC2:C35 Binding Site For Residue D 1433'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V22 OCA].
+V22 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=C35:'>C35</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Known structural/functional Sites: <scene name='pdbsite=AC1:C35+Binding+Site+For+Residue+B+1433'>AC1</scene> and <scene name='pdbsite=AC2:C35+Binding+Site+For+Residue+D+1433'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V22 OCA].
 ==Reference==
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 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Protein complex]]
-[[Category: Andrews, M.J.]]
+[[Category: Andrews, M J.]]
 [[Category: Cowan, A.]]
-[[Category: Fischer, P.M.]]
+[[Category: Fischer, P M.]]
 [[Category: Innes, L.]]
 [[Category: Jewsbury, P.]]
@@ Line 40: / Line 40: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jan 31 11:01:33 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:52:39 2008''