title: An NMR-based scoring function improves the accuracy of binding pose predictions by docking by two orders of magnitude.
abstract: Low-affinity ligands can be efficiently optimized into high-affinity drug leads by structure based drug design when atomic-resolution structural information on the protein/ligand complexes is available. In this work we show that the use of a few, easily obtainable, experimental restraints improves the accuracy of the docking experiments by two orders of magnitude. The experimental data are measured in nuclear magnetic resonance spectra and consist of protein-mediated NOEs between two competitively binding ligands. The methodology can be widely applied as the data are readily obtained for low-affinity ligands in the presence of non-labelled receptor at low concentration. The experimental inter-ligand NOEs are efficiently used to filter and rank complex model structures that have been pre-selected by docking protocols. This approach dramatically reduces the degeneracy and inaccuracy of the chosen model in docking experiments, is robust with respect to inaccuracy of the structural model used to represent the free receptor and is suitable for high-throughput docking campaigns.
authors.affiliation: EMBL, Structure and Computational Biology Unit, Meyerhofstrasse 1, 69117, Heidelberg, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Orts
authors.forename: Stefan
authors.initials: S
authors.lastname: Bartoschek
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Peter
authors.initials: P
authors.lastname: Monecke
authors.forename: Teresa
authors.initials: T
authors.lastname: Carlomagno
mesh_terms: D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011506:Proteins; D017868:Cyclic AMP-Dependent Protein Kinases