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

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 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.

LanguageEnglish
Pages8982-8988
JournalJournal of Medicinal Chemistry
Volume60
Early online date13 Oct 2017
DOIs
Publication statusPublished - 13 Oct 2017

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Peptides
Proteins
Digital Libraries
Amino Acids
Workflow
X Ray Crystallography
Ligands

Keywords

  • Journal Article

Cite this

Krüger, Dennis M ; Glas, Adrian ; Bier, David ; Pospiech, Nicole ; Wallraven, Kerstin ; Dietrich, Laura ; Ottmann, Christian ; Koch, Oliver ; Hennig, Sven ; Grossmann, Tom N. / Structure-Based Design of Non-Natural Macrocyclic Peptides that Inhibit Protein-Protein Interactions. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60. pp. 8982-8988.
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Structure-Based Design of Non-Natural Macrocyclic Peptides that Inhibit Protein-Protein Interactions. / Krüger, Dennis M; Glas, Adrian; Bier, David; Pospiech, Nicole; Wallraven, Kerstin; Dietrich, Laura; Ottmann, Christian; Koch, Oliver; Hennig, Sven; Grossmann, Tom N.

In: Journal of Medicinal Chemistry, Vol. 60, 13.10.2017, p. 8982-8988.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Wallraven, Kerstin

AU - Dietrich, Laura

AU - Ottmann, Christian

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AU - Grossmann, Tom N

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N2 - 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.

AB - 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.

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