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Nanodiscs for INPHARMA NMR Characterization of GPCRs: Ligand Binding to the Human A2A Adenosine Receptor
Author(s) -
Fredriksson Kai,
Lottmann Philip,
Hinz Sonja,
Onila Iounut,
Shymanets Aliaksei,
Harteneck Christian,
Müller Christa E.,
Griesinger Christian,
Exner Thomas E.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201612547
Subject(s) - pharmacophore , g protein coupled receptor , ligand (biochemistry) , chemistry , adenosine receptor , adenosine a2a receptor , stereochemistry , drug discovery , receptor , combinatorial chemistry , computational biology , biophysics , biochemistry , biology , agonist
G‐protein‐coupled‐receptors (GPCRs) are of fundamental importance for signal transduction through cell membranes. This makes them important drug targets, but structure‐based drug design (SBDD) is still hampered by the limitations for structure determination of unmodified GPCRs. We show that the interligand NOEs for pharmacophore mapping (INPHARMA) method can provide valuable information on ligand poses inside the binding site of the unmodified human A 2A adenosine receptor reconstituted in nanodiscs. By comparing experimental INPHARMA spectra with back‐calculated spectra based on ligand poses obtained from molecular dynamics simulations, a complex structure for A 2A R with the low‐affinity ligand 3‐pyrrolidin‐1‐ylquinoxalin‐2‐amine was determined based on the X‐ray structure of ligand ZM‐241,358 in complex with a modified A 2A R.