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Publication Abstract from PubMed

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.

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.