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Fast NMR‐Based Determination of the 3D Structure of the Binding Site of Protein–Ligand Complexes with Weak Affinity Binders
Author(s) -
Wälti Marielle A.,
Riek Roland,
Orts Julien
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201612304
Subject(s) - ligand (biochemistry) , chemistry , drug discovery , protein structure , protein ligand , resolution (logic) , crystallography , structural bioinformatics , nuclear magnetic resonance spectroscopy , combinatorial chemistry , stereochemistry , computer science , biochemistry , receptor , artificial intelligence
In early drug discovery approaches, screening hits are often weak affinity binders that are difficult to characterize in structural detail, particularly towards obtaining the 3D structure of protein–ligand complexes at atomic resolution. NMR is the outstanding technique to tackle such problems, yet suffers from a tedious structure calculation process. N MR 2 was recently developed to alleviate the laborious element of routine NMR structure calculation procedures and provides the structural information at protein–ligand interaction sites orders of magnitude faster than standard procedures. The N MR 2 method was extended to weak binders and applied to the oncoproteins HDM2 and MDMX. The structure of the MDMX‐SJ212 complex is reported with a K d of approximately 0.7 μ m ; the complex structure of HDM2 with the m m affinity ligand #845 exhibits a new scaffold.