dc.creator | Andrews, M. J. I. | en |
dc.creator | Kontopidis, G. | en |
dc.creator | McInnes, C. | en |
dc.creator | Plater, A. | en |
dc.creator | Innes, L. | en |
dc.creator | Cowan, A. | en |
dc.creator | Jewsbury, P. | en |
dc.creator | Fischer, P. M. | en |
dc.date.accessioned | 2015-11-23T10:22:20Z | |
dc.date.available | 2015-11-23T10:22:20Z | |
dc.date.issued | 2006 | |
dc.identifier | 10.1002/cbic.200600189 | |
dc.identifier.issn | 14394227 | |
dc.identifier.uri | http://hdl.handle.net/11615/25595 | |
dc.description.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. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA. | en |
dc.source | ChemBioChem | en |
dc.source.uri | http://www.scopus.com/inward/record.url?eid=2-s2.0-33845395240&partnerID=40&md5=e3fa6a06b8e86c0111c523aa09206b62 | |
dc.subject | Capping groups | en |
dc.subject | Crystal structure | en |
dc.subject | Cyclin A | en |
dc.subject | Inhibitors | en |
dc.subject | Peptidomimetics | en |
dc.subject | Virtual screening | en |
dc.subject | amino acid derivative | en |
dc.subject | cyclin dependent kinase 2 | en |
dc.subject | diphenyl ether derivative | en |
dc.subject | phenyltriazole | en |
dc.subject | triazole derivative | en |
dc.subject | article | en |
dc.subject | binding assay | en |
dc.subject | chemical structure | en |
dc.subject | priority journal | en |
dc.subject | protein binding | en |
dc.subject | protein protein interaction | en |
dc.subject | X ray crystallography | en |
dc.subject | Amino Acid Substitution | en |
dc.subject | Binding Sites | en |
dc.subject | Crystallography, X-Ray | en |
dc.subject | Cyclin-Dependent Kinase Inhibitor p21 | en |
dc.subject | Drug Design | en |
dc.subject | Molecular Structure | en |
dc.subject | Peptide Library | en |
dc.subject | Peptides | en |
dc.subject | Protein Engineering | en |
dc.title | REPLACE: A strategy for iterative design of cyclin-binding groove inhibitors | en |
dc.type | journalArticle | en |