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ID: ALA4219221
Journal: Bioorg Med Chem
Title: Thioamide substitution to probe the hydroxyproline recognition of VHL ligands.
Authors: Soares P, Lucas X, Ciulli A.
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.
CiteXplore: 29650462