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Thioamide substitution to probe the hydroxyproline recognition of VHL ligands

DOI: 10.1016/j.bmc.2018.03.034 DOI Help

Authors: Pedro Soares (University of Dundee) , Xavier Lucas (University of Dundee) , Alessio Ciulli (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry

State: Published (Approved)
Published: March 2018
Diamond Proposal Number(s): 10071

Open Access Open Access

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.

Journal Keywords: Protein-ligand interactions; VHL ligands; Thioamides; n→π∗interaction; PROTACs

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 27/03/2018 15:41


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)