2v22 | pdb_00002v22
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| 2v22, resolution 2.60Å | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sites: | AC1 and AC2 | ||||||||||||
| Ligands: | C35 | ||||||||||||
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
REPLACE: A STRATEGY FOR ITERATIVE DESIGN OF CYCLIN BINDING GROOVE INHIBITORS
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.
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
Page seeded by OCA on Thu Mar 20 18:42:28 2008
Proteopedia Page Contributors and Editors (what is this?)
- Pages with broken file links
- Homo sapiens
- Non-specific serine/threonine protein kinase
- Protein complex
- Andrews, M J.
- Cowan, A.
- Fischer, P M.
- Innes, L.
- Jewsbury, P.
- Kontopidis, G.
- Mcinnes, C.
- Plater, A.
- C35
- Active
- Atp-binding
- Cdk2
- Cell cycle
- Cell division
- Cyclin
- Cyclin groove
- Inhibition
- Kinase
- Mitosis
- Nonpeptide
- Nucleotide-binding
- Phosphorylation
- Polymorphism
- Serine/threonine-protein kinase
- Transferase
