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Design Of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization
- Source :
- Chemistry - A European Journal, Wiley-VCH Verlag, 2020, 26 (31), pp.7131-7139
- Publication Year :
- 2020
-
Abstract
- The 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 study 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 Mg 2+ 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.
- Subjects :
- Quantitative Biology - Biomolecules
Subjects
Details
- Database :
- arXiv
- Journal :
- Chemistry - A European Journal, Wiley-VCH Verlag, 2020, 26 (31), pp.7131-7139
- Publication Type :
- Report
- Accession number :
- edsarx.2011.03419
- Document Type :
- Working Paper
- Full Text :
- https://doi.org/10.1002/chem.202001608