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Query-guided protein–protein interaction inhibitor discovery

DOI: 10.1039/D1SC00023C DOI Help

Authors: Sergio Celis (University of Leeds) , Fruzsina Hobor (University of Leeds) , Thomas James (University of Leeds) , Gail J. Bartlett (University of Bristol) , Amaurys A. Ibarra (University of Bristol) , Deborah K. Shoemark (University of Bristol) , Zsofia Hegedus (University of Leeds) , Kristina Hetherington (University of Leeds) , Derek N. Woolfson (University of Bristol) , Richard B. Sessions (University of Bristol) , Thomas A. Edwards (University of Leeds) , David M. Andrews (AstraZeneca) , Adam Nelson (University of Leeds) , Andrew J. Wilson (University of Leeds)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Chemical Science , VOL 19

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 19248

Open Access Open Access

Abstract: Protein–protein interactions (PPIs) are central to biological mechanisms, and can serve as compelling targets for drug discovery. Yet, the discovery of small molecule inhibitors of PPIs remains challenging given the large and typically shallow topography of the interacting protein surfaces. Here, we describe a general approach to the discovery of orthosteric PPI inhibitors that mimic specific secondary protein structures. Initially, hot residues at protein–protein interfaces are identified in silico or from experimental data, and incorporated into secondary structure-based queries. Virtual libraries of small molecules are then shape-matched against the queries, and promising ligands docked to target proteins. The approach is exemplified experimentally using two unrelated PPIs that are mediated by an α-helix (p53/hDM2) and a β-strand (GKAP/SHANK1-PDZ). In each case, selective PPI inhibitors are discovered with low μM activity as determined by a combination of fluorescence anisotropy and 1H–15N HSQC experiments. In addition, hit expansion yields a series of PPI inhibitors with defined structure–activity relationships. It is envisaged that the generality of the approach will enable discovery of inhibitors of a wide range of unrelated secondary structure-mediated PPIs.

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

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)