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J Med Chem. 2017 Nov 9;60(21):8982-8988. doi: 10.1021/acs.jmedchem.7b01221. Epub 2017 Oct 27.

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

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Chemical Genomics Centre of the Max Planck Society , Otto-Hahn-Str. 15, 44227 Dortmund, Germany.
Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Str. 6, 44227 Dortmund, Germany.
Department of Chemistry, University of Duisburg-Essen , Universitätstr. 7, 45141 Essen, Germany.
Department of Biomedical Engineering, Institute of Complex Molecular Systems, Eindhoven University of Technology , Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
Department of Chemistry & Pharmaceutical Sciences, VU University Amsterdam , De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.


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.

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