Structure-Based Design of Non-Natural Macrocyclic Peptides that Inhibit Protein-Protein Interactions

Dennis M Krüger, Adrian Glas, David Bier, Nicole Pospiech, Kerstin Wallraven, Laura Dietrich, Christian Ottmann, Oliver Koch, Sven Hennig, Tom N Grossmann

Research output: Contribution to JournalArticleAcademicpeer-review


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 which 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.

Original languageEnglish
Pages (from-to)8982-8988
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number21
Early online date13 Oct 2017
Publication statusPublished - 13 Oct 2017


  • Journal Article


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