title: REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors.
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.
authors.affiliation: Cyclacel Limited, James Lindsay Place, Dundee, DD1 5JJ, UK. martin.andrews@glpg.com
authors.forename: Martin J I
authors.initials: MJ
authors.lastname: Andrews
authors.forename: George
authors.initials: G
authors.lastname: Kontopidis
authors.forename: Campbell
authors.initials: C
authors.lastname: McInnes
authors.forename: Andy
authors.initials: A
authors.lastname: Plater
authors.forename: Lorraine
authors.initials: L
authors.lastname: Innes
authors.forename: Angela
authors.initials: A
authors.lastname: Cowan
authors.forename: Philip
authors.initials: P
authors.lastname: Jewsbury
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000737:chemistry*; D015195:Drug Design; D015394:Molecular Structure; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015202:Protein Engineering / Q000379:methods*
chemical_list: D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019151:Peptide Library; D010455:Peptides