Abstract
Protein–protein interactions (PPIs) provide a rich source of potential targets for drug discovery and biomedical science research. However, the identification of structural-diverse starting points for discovery of PPI inhibitors remains a significant challenge. Activity-directed synthesis (ADS), a function-driven discovery approach, was harnessed in the discovery of the p53/hDM2 PPI. Over two rounds of ADS, 346 microscale reactions were performed, with prioritisation on the basis of the activity of the resulting product mixtures. Four distinct and novel series of PPI inhibitors were discovered that, through biophysical characterisation, were shown to have promising ligand efficiencies. It was thus shown that ADS can facilitate ligand discovery for a target that does not have a defined small-molecule binding site, and can provide distinctive starting points for the discovery of PPI inhibitors.
Original language | English |
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Pages (from-to) | 10682-10689 |
Number of pages | 8 |
Journal | Chemistry - A European Journal |
Volume | 26 |
Issue number | 47 |
DOIs | |
Publication status | Published - 21 Aug 2020 |
Bibliographical note
Funding Information:We thank EPSRC (EP/N013573/1 and Established Career Fellowship EP/N025652/1 to A.N.), GSK (iCASE studentship, A.I.G.) and the Leverhulme Trust (Senior Fellowship SRF\R1\191087 to A.J.W) for funding. We also thank Mark Howard, George Karageorgis, Ian Churcher and Thomas Edwards for their insight and helpful discussion, and Pallavi Ramsahye for help with protein expression.
Publisher Copyright:
© 2020 The Authors. Published by Wiley-VCH GmbH
Keywords
- lead discovery
- metal carbenoids
- molecular diversity
- protein–protein interactions
- scaffold hopping
ASJC Scopus subject areas
- Catalysis
- General Chemistry
- Organic Chemistry