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ID: ALA4024750

Journal: J Med Chem

Title: Structure-Based Design of Non-natural Macrocyclic Peptides That Inhibit Protein-Protein Interactions.

Authors: Krüger DM, Glas A, Bier D, Pospiech N, Wallraven K, Dietrich L, Ottmann C, Koch O, Hennig S, Grossmann TN.

Abstract: Macrocyclic peptides can interfere with challenging biomolecular targets including protein-protein interactions. Whereas there are various approaches that facilitate the identification of peptide-derived ligands, their evolution into higher affinity binders remains a major hurdle. We report a virtual screen based on molecular docking that allows the affinity maturation of macrocyclic peptides taking non-natural amino acids into consideration. These macrocycles bear large and flexible substituents that usually complicate the use of docking approaches. A virtual library containing more than 1400 structures was screened against the target focusing on docking poses with the core structure resembling a known bioactive conformation. Based on this screen, a macrocyclic peptide 22 involving two non-natural amino acids was evolved showing increased target affinity and biological activity. Predicted binding modes were verified by X-ray crystallography. The presented workflow allows the screening of large macrocyclic peptides with diverse modifications thereby expanding the accessible chemical space and reducing synthetic efforts.

CiteXplore: 29028171

DOI: 10.1021/acs.jmedchem.7b01221