Inhibitor discovery for protein-protein interactions has proven difficult due to the large protein surface areas and dynamic interfaces. To address this challenge, structural biology approaches for ligand discovery have had a significant impact on advancing small molecule inhibitors into the clinic. Inspired by the protein-observed NMR approach using 1H-15N-HSQC NMR, we have applied a complementary protein-observed 19F NMR (PrOF NMR) approach using 19F-labeled side-chains that are enriched at protein-protein-interaction interfaces. This talk will describe several case studies where PrOF NMR has been applied for fragment screening, ligand deconstruction, and screening of protein mixtures. Several new inhibitors of epigenetic complexes involving bromodomain-containing proteins will also be highlighted.

SAR by 19F NMR: Using protein-observed fluorine NMR for targeting protein complexes

ACS Fall 2020 Virtual Meeting

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