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  Competition NMR for Detection of Hit/Lead Inhibitors of Protein-Protein Interactions

Musielak, B., Janczyk, W., Rodriguez, I., Plewka, J., Sala, D., Magiera-Mularz, K., et al. (2020). Competition NMR for Detection of Hit/Lead Inhibitors of Protein-Protein Interactions. Molecules, 25(13): 3017. doi:10.3390/molecules25133017.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0007-8C88-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0007-8C89-1
Genre: Journal Article

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 Creators:
Musielak, Bogdan1, Author
Janczyk, Weronika2, Author              
Rodriguez, Ismael1, Author
Plewka, Jacek1, Author
Sala, Dominik1, Author
Magiera-Mularz, Katarzyna1, Author
Holak, Tad2, Author              
Affiliations:
1external, ou_persistent22              
2Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565154              

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Free keywords: CANCER-IMMUNOTHERAPY; LIGAND-BINDING; DRUG DISCOVERY; DEATH 1; P53; MDM2; ANTAGONISTS; DESIGN; PD-1; SARBiochemistry & Molecular Biology; Chemistry; NMR; Mdm2; p53; PD-1; PD-L1; protein-protein interaction; small molecule;
 Abstract: Screening for small-molecule fragments that can lead to potent inhibitors of protein-protein interactions (PPIs) is often a laborious step as the fragments cannot dissociate the targeted PPI due to their low mu M-mM affinities. Here, we describe an NMR competition assay called w-AIDA-NMR (weak-antagonist induced dissociation assay-NMR), which is sensitive to weak mu M-mM ligand-protein interactions and which can be used in initial fragment screening campaigns. By introducing point mutations in the complex's protein that is not targeted by the inhibitor, we lower the effective affinity of the complex, allowing for short fragments to dissociate the complex. We illustrate the method with the compounds that block the Mdm2/X-p53 and PD-1/PD-L1 oncogenic interactions. Targeting the PD-/PD-L1 PPI has profoundly advanced the treatment of different types of cancers.

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Language(s): eng - English
 Dates: 2020
 Publication Status: Published online
 Pages: 16
 Publishing info: -
 Table of Contents: (This article belongs to the Special Issue NMR in the Drug Design)
 Rev. Type: -
 Identifiers: ISI: 000550347700001
DOI: 10.3390/molecules25133017
 Degree: -

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Title: Molecules
Source Genre: Journal
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Publ. Info: Basel : MDPI
Pages: - Volume / Issue: 25 (13) Sequence Number: 3017 Start / End Page: - Identifier: ISSN: 1420-3049
CoNE: https://pure.mpg.de/cone/journals/resource/954925623244