PI by NMR: Probing CH-? Interactions in Protein-Ligand Complexes by NMR Spectroscopy.

ABSTRACT: While CH-? 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-? interactions in drug-protein complexes. Herein, we present a fast and reliable methodology called PI (? interactions) by NMR, which can differentiate the strength of protein-ligand CH-? interactions in solution. By combining selective amino-acid side-chain labeling with 1 H-13 C?NMR, we are able to identify specific protein protons of side-chains engaged in CH-? interactions with aromatic ring systems of a ligand, based solely on 1 H 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-? interaction. PI by NMR changes the paradigm by which chemists can optimize the potency of drug candidates: direct determination of individual ? interactions rather than averaged measures of all interactions.

SUBMITTER: Platzer G 

PROVIDER: S-EPMC7496880 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature