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spinqualitylabelsall models 2v22, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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 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.

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

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