2V22: Replace: A Strategy For Iterative Design Of Cyclin Binding Groove Inhibitors

Citation:
Abstract
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.
PDB ID: 2V22Download
MMDB ID: 62126
PDB Deposition Date: 2007/5/31
Updated in MMDB: 2011/10
Experimental Method:
x-ray diffraction
Resolution: 2.6  Å
Source Organism:
Similar Structures:
Biological Unit for 2V22: tetrameric; determined by author and by software (PQS)
Molecular Components in 2V22
Label Count Molecule
Proteins (4 molecules)
2
Cell Division Protein Kinase 2(Gene symbol: CDK2)
Molecule annotation
2
Cyclin-a2(Gene symbol: CCNA2)
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

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