title: A combination of spin diffusion methods for the determination of protein-ligand complex structural ensembles.
abstract: Structure-based drug design (SBDD) is a powerful and widely used approach to optimize affinity of drug candidates. With the recently introduced INPHARMA method, the binding mode of small molecules to their protein target can be characterized even if no spectroscopic information about the protein is known. Here, we show that the combination of the spin-diffusion-based NMR methods INPHARMA, trNOE, and STD results in an accurate scoring function for docking modes and therefore determination of protein-ligand complex structures. Applications are shown on the model system protein kinase A and the drug targets glycogen phosphorylase and soluble epoxide hydrolase (sEH). Multiplexing of several ligands improves the reliability of the scoring function further. The new score allows in the case of sEH detecting two binding modes of the ligand in its binding site, which was corroborated by X-ray analysis.
authors: Abteilung für NMR-basierte Strukturbiologie, Max-Planck-Institut für biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany).
authors: Jens
authors: J
authors: Pilger
authors: Abteilung für NMR-basierte Strukturbiologie, Max-Planck-Institut für biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany).
authors: Adam
authors: A
authors: Mazur
authors: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt a. M. (Germany).
authors: Peter
authors: P
authors: Monecke
authors: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt a. M. (Germany).
authors: Herman
authors: H
authors: Schreuder
authors: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt a. M. (Germany).
authors: Bettina
authors: B
authors: Elshorst
authors: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt a. M. (Germany).
authors: Stefan
authors: S
authors: Bartoschek
authors: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt a. M. (Germany).
authors: Thomas
authors: T
authors: Langer
authors: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt a. M. (Germany).
authors: Alexander
authors: A
authors: Schiffer
authors: Université Claude Bernard Lyon1, Villeurbanne Cedex (France).
authors: Isabelle
authors: I
authors: Krimm
authors: Abteilung für NMR-basierte Strukturbiologie, Max-Planck-Institut für biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany).
authors: Melanie
authors: M
authors: Wegstroth
authors: Abteilung für NMR-basierte Strukturbiologie, Max-Planck-Institut für biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany).
authors: Donghan
authors: D
authors: Lee
authors: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt a. M. (Germany).
authors: Gerhard
authors: G
authors: Hessler
authors: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt a. M. (Germany).
authors: K-Ulrich
authors: KU
authors: Wendt
authors: Abteilung für NMR-basierte Strukturbiologie, Max-Planck-Institut für biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany).
authors: Stefan
authors: S
authors: Becker
authors: Abteilung für NMR-basierte Strukturbiologie, Max-Planck-Institut für biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany). cigr@nmr.mpibpc.mpg.de.
authors: Christian
authors: C
authors: Griesinger
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004058:Diffusion; D015195:Drug Design; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D011506:Proteins; D024981:Glycogen Phosphorylase; D017868:Cyclic AMP-Dependent Protein Kinases; D004851:Epoxide Hydrolases
keywords: NMR spectroscopy; drug design; glycogen phosphorylase; kinases; soluble epoxide hydrolase