Celis, S orcid.org/0000-0001-8177-2472, Hobor, F, James, T et al. (11 more authors) (2021) Query-Guided Protein-Protein Interaction Inhibitor Discovery. Chemical Science, 12 (13). pp. 4753-4762. ISSN 2041-6520
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Author(s). Published by the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Crystallography (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Feb 2021 14:51 |
Last Modified: | 08 Mar 2022 10:36 |
Status: | Published |
Publisher: | Royal Society of Chemistry |
Identification Number: | 10.1039/D1SC00023C |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:171361 |