title: Fast NMR-Based Determination of the 3D Structure of the Binding Site of Protein-Ligand Complexes with Weak Affinity Binders.
abstract: 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. NMR2was 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 NMR2method was extended to weak binders and applied to the oncoproteins HDM2 and MDMX. The structure of the MDMX-SJ212 complex is reported with a Kdof approximately 0.7 μm; the complex structure of HDM2 with the mm affinity ligand #845 exhibits a new scaffold.
authors.affiliation: Laboratorium für Physikalische Chemie, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.
authors.forename: Marielle A
authors.initials: MA
authors.lastname: Wälti
authors.affiliation: Laboratorium für Physikalische Chemie, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
authors.affiliation: Laboratorium für Physikalische Chemie, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.
authors.forename: Julien
authors.identifier: 0000-0003-3287-1532
authors.initials: J
authors.lastname: Orts
keywords: NMR spectroscopy; NMR2; drug design; structure elucidation; structure-activity relationships