| Autor: |
Krüger, Dennis M., Glas, Adrian, Bier, David, Pospiech, Nicole, Wallraven, Kerstin, Dietrich, Laura, Ottmann, Christian, Koch, Oliver, Hennig, Sven, Grossmann, Tom N. |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
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 22involving 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. |
| Databáze: |
Supplemental Index |
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