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Thioamide substitution to probe the hydroxyproline recognition of VHL ligands.
- Source :
-
Bioorganic & Medicinal Chemistry . Jul2018, Vol. 26 Issue 11, p2992-2995. 4p. - Publication Year :
- 2018
-
Abstract
- Thioamide substitution influences hydrogen bond and n → π ∗ interactions involved in the conformational stability of protein secondary structures and oligopeptides. Hydroxyproline is the key recognition element of small molecules targeting the von Hippel-Lindau (VHL) E3 ligase, which are of interest as probes of hypoxia signaling and ligands for PROTAC conjugation. We hypothesized that VHL ligands could be a privileged model system to evaluate the contribution of these interactions to protein:ligand complex formation. Herein we report the synthesis of VHL ligands bearing thioamide substitutions at the central hydroxyproline moiety, and characterize their binding by fluorescence polarization, isothermal titration calorimetry, X-ray crystallography and molecular modeling. In spite of a conserved binding mode, the substitution pattern had a pronounced impact on the ligand affinities. Together the results underscore the role of hydrogen bond and n → π ∗ interactions in fine tuning hydroxyproline recognition by VHL. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 26
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 129995953
- Full Text :
- https://doi.org/10.1016/j.bmc.2018.03.034