title: Accounting for conformational variability in protein-ligand docking with NMR-guided rescoring.
abstract: A key component to success in structure-based drug design is reliable information on protein-ligand interactions. Recent development in NMR techniques has accelerated this process by overcoming some of the limitations of X-ray crystallography and computational protein-ligand docking. In this work we present a new scoring protocol based on NMR-derived interligand INPHARMA NOEs to guide the selection of computationally generated docking modes. We demonstrate the performance in a range of scenarios, encompassing traditionally difficult cases such as docking to homology models and ligand dependent domain rearrangements. Ambiguities associated with sparse experimental information are lifted by searching a consensus solution based on simultaneously fitting multiple ligand pairs. This study provides a previously unexplored integration between molecular modeling and experimental data, in which interligand NOEs represent the key element in the rescoring algorithm. The presented protocol should be widely applicable for protein-ligand docking also in a different context from drug design and highlights the important role of NMR-based approaches to describe intermolecular ligand-receptor interactions.
authors.affiliation: EMBL, Structural and Computational Biology Unit, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Skjærven
authors.forename: Luca
authors.initials: L
authors.lastname: Codutti
authors.forename: Andrea
authors.initials: A
authors.lastname: Angelini
authors.forename: Manuela
authors.initials: M
authors.lastname: Grimaldi
authors.forename: Dorota
authors.initials: D
authors.lastname: Latek
authors.forename: Peter
authors.initials: P
authors.lastname: Monecke
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Dreyer
authors.forename: Teresa
authors.initials: T
authors.lastname: Carlomagno
mesh_terms: D000818:Animals; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases