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6938296 
Journal Article 
PI by NMR: Probing CH-pi Interactions in Protein-Ligand Complexes by NMR Spectroscopy 
Platzer, G; Lichtenecker, R; Wolkerstorfer, B; Kessler, D; Mcconnell, DB; Konrat, R; Mayer, M; Beier, A; Brueschweiler, S; Fuchs, JE; Engelhardt, H; Geist, L; Bader, G; Schoerghuber, J; , 
2020 
Yes 
Angewandte Chemie (International Edition)
ISSN: 1433-7851
EISSN: 1521-3773 
WILEY-V C H VERLAG GMBH 
WEINHEIM 
14861-14868 
32421895 
WOS:000548332100001 
While CH-pi interactions with target proteins are crucial determinants for the affinity of arguably every drug molecule, no method exists to directly measure the strength of individual CH-pi interactions in drug-protein complexes. Herein, we present a fast and reliable methodology called PI (pi interactions) by NMR, which can differentiate the strength of protein-ligand CH-pi interactions in solution. By combining selective amino-acid side-chain labeling with H-1-C-1(3) NMR, we are able to identify specific protein protons of side-chains engaged in CH-pi interactions with aromatic ring systems of a ligand, based solely on H-1 chemical-shift values of the interacting protein aromatic ring protons. The information encoded in the chemical shifts induced by such interactions serves as a proxy for the strength of each individual CH-pi interaction. PI by NMR changes the paradigm by which chemists can optimize the potency of drug candidates: direct determination of individual pi interactions rather than averaged measures of all interactions.