期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 26, 期 31, 页码 7131-7139出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202001608
关键词
chelates; drug design; medicinal chemistry; PAINS; protein-protein interaction stabilization
资金
- Initial Training Network TASPPI - H2020 Marie Sklodowska-Curie Actions of the European Commission [675179]
- Nord Region Council, CNRS, Institut Pasteur de Lille
- European Community (ERDF)
- French Ministry of Research
- University of Lille
- CTRL CPER
- European Union
- European Regional Development Fund (ERDF)
- Hauts de France Regional Council [17003781]
- Metropole Europenne de Lille [2016 ESR 05]
- French State [2017-R3-CTRL-Phase 1]
Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg2+ leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective, and drug-like 14-3-3 PPI stabilizers.
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