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PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy

While CH–π 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–π interactions in drug–protein complexes. Herein, we present a fast and reliable methodology called PI (π interac...

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Autores principales: Platzer, Gerald, Mayer, Moriz, Beier, Andreas, Brüschweiler, Sven, Fuchs, Julian E., Engelhardt, Harald, Geist, Leonhard, Bader, Gerd, Schörghuber, Julia, Lichtenecker, Roman, Wolkerstorfer, Bernhard, Kessler, Dirk, McConnell, Darryl B., Konrat, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496880/
https://www.ncbi.nlm.nih.gov/pubmed/32421895
http://dx.doi.org/10.1002/anie.202003732
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author Platzer, Gerald
Mayer, Moriz
Beier, Andreas
Brüschweiler, Sven
Fuchs, Julian E.
Engelhardt, Harald
Geist, Leonhard
Bader, Gerd
Schörghuber, Julia
Lichtenecker, Roman
Wolkerstorfer, Bernhard
Kessler, Dirk
McConnell, Darryl B.
Konrat, Robert
author_facet Platzer, Gerald
Mayer, Moriz
Beier, Andreas
Brüschweiler, Sven
Fuchs, Julian E.
Engelhardt, Harald
Geist, Leonhard
Bader, Gerd
Schörghuber, Julia
Lichtenecker, Roman
Wolkerstorfer, Bernhard
Kessler, Dirk
McConnell, Darryl B.
Konrat, Robert
author_sort Platzer, Gerald
collection PubMed
description While CH–π 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–π interactions in drug–protein complexes. Herein, we present a fast and reliable methodology called PI (π interactions) by NMR, which can differentiate the strength of protein–ligand CH–π 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–π 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–π interaction. PI by NMR changes the paradigm by which chemists can optimize the potency of drug candidates: direct determination of individual π interactions rather than averaged measures of all interactions.
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spelling pubmed-74968802020-09-25 PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy Platzer, Gerald Mayer, Moriz Beier, Andreas Brüschweiler, Sven Fuchs, Julian E. Engelhardt, Harald Geist, Leonhard Bader, Gerd Schörghuber, Julia Lichtenecker, Roman Wolkerstorfer, Bernhard Kessler, Dirk McConnell, Darryl B. Konrat, Robert Angew Chem Int Ed Engl Research Articles While CH–π 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–π interactions in drug–protein complexes. Herein, we present a fast and reliable methodology called PI (π interactions) by NMR, which can differentiate the strength of protein–ligand CH–π 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–π 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–π interaction. PI by NMR changes the paradigm by which chemists can optimize the potency of drug candidates: direct determination of individual π interactions rather than averaged measures of all interactions. John Wiley and Sons Inc. 2020-07-15 2020-08-24 /pmc/articles/PMC7496880/ /pubmed/32421895 http://dx.doi.org/10.1002/anie.202003732 Text en © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Platzer, Gerald
Mayer, Moriz
Beier, Andreas
Brüschweiler, Sven
Fuchs, Julian E.
Engelhardt, Harald
Geist, Leonhard
Bader, Gerd
Schörghuber, Julia
Lichtenecker, Roman
Wolkerstorfer, Bernhard
Kessler, Dirk
McConnell, Darryl B.
Konrat, Robert
PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy
title PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy
title_full PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy
title_fullStr PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy
title_full_unstemmed PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy
title_short PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy
title_sort pi by nmr: probing ch–π interactions in protein–ligand complexes by nmr spectroscopy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496880/
https://www.ncbi.nlm.nih.gov/pubmed/32421895
http://dx.doi.org/10.1002/anie.202003732
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