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Article

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

1
Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland
2
Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Simona Golič Grdadolnik
Molecules 2020, 25(13), 3017; https://doi.org/10.3390/molecules25133017
Received: 17 June 2020 / Revised: 28 June 2020 / Accepted: 29 June 2020 / Published: 1 July 2020
(This article belongs to the Special Issue NMR in the Drug Design)
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 μM–mM affinities. Here, we describe an NMR competition assay called w-AIDA-NMR (weak-antagonist induced dissociation assay-NMR), which is sensitive to weak μM–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. View Full-Text
Keywords: NMR; Mdm2/p53; PD-1/PD-L1; protein–protein interaction; small molecule NMR; Mdm2/p53; PD-1/PD-L1; protein–protein interaction; small molecule
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MDPI and ACS Style

Musielak, B.; Janczyk, W.; Rodriguez, I.; Plewka, J.; Sala, D.; Magiera-Mularz, K.; Holak, T. Competition NMR for Detection of Hit/Lead Inhibitors of Protein–Protein Interactions. Molecules 2020, 25, 3017. https://doi.org/10.3390/molecules25133017

AMA Style

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

Chicago/Turabian Style

Musielak, Bogdan, Weronika Janczyk, Ismael Rodriguez, Jacek Plewka, Dominik Sala, Katarzyna Magiera-Mularz, and Tad Holak. 2020. "Competition NMR for Detection of Hit/Lead Inhibitors of Protein–Protein Interactions" Molecules 25, no. 13: 3017. https://doi.org/10.3390/molecules25133017

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