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REPLACE: A Strategy for Iterative Design of Cyclin‐Binding Groove Inhibitors
Author(s) -
Andrews Martin J. I.,
Kontopidis George,
McInnes Campbell,
Plater Andy,
Innes Lorraine,
Cowan Angela,
Jewsbury Philip,
Fischer Peter M.
Publication year - 2006
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200600189
Subject(s) - pentapeptide repeat , peptide , chemistry , in silico , small molecule , docking (animal) , combinatorial chemistry , binding site , stereochemistry , rational design , lead compound , computational biology , biochemistry , biology , in vitro , medicine , genetics , nursing , gene
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.