Issue 13, 2021

Query-guided protein–protein interaction inhibitor discovery


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.

Graphical abstract: Query-guided protein–protein interaction inhibitor discovery

Supplementary files

Article information

Article type
Edge Article
03 Jan 2021
19 Feb 2021
First published
02 Mar 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 4753-4762

Query-guided protein–protein interaction inhibitor discovery

S. Celis, F. Hobor, T. James, G. J. Bartlett, A. A. Ibarra, D. K. Shoemark, Z. Hegedüs, K. Hetherington, D. N. Woolfson, R. B. Sessions, T. A. Edwards, D. M. Andrews, A. Nelson and A. J. Wilson, Chem. Sci., 2021, 12, 4753 DOI: 10.1039/D1SC00023C

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