title: Ligand Residence Time at G-protein-Coupled Receptors-Why We Should Take Our Time To Study It.
abstract: Over the past decade the kinetics of ligand binding to a receptor have received increasing interest. The concept of drug-target residence time is becoming an invaluable parameter for drug optimization. It holds great promise for drug development, and its optimization is thought to reduce off-target effects. The success of long-acting drugs like tiotropium support this hypothesis. Nonetheless, we know surprisingly little about the dynamics and the molecular detail of the drug binding process. Because protein dynamics and adaptation during the binding event will change the conformation of the protein, ligand binding will not be the static process that is often described. This can cause problems because simple mathematical models often fail to adequately describe the dynamics of the binding process. In this minireview we will discuss the current situation with an emphasis on G-protein-coupled receptors. These are important membrane protein drug targets that undergo conformational changes upon agonist binding to communicate signaling information across the plasma membrane of cells.
authors.affiliation: Bio-Imaging-Center/Rudolf-Virchow-Zentrum and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.H.); Molecular Pharmacology Laboratory, Biofarma Research Group (GI-1685), University of Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Spain (M.C.); Institute of Chemistry, University of Tartu, Tartu, Estonia (A.R.); Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University, Amsterdam, Amsterdam, The Netherlands (R.L., H.F.V.); and Cell Signalling Research Group, School of Life Sciences, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom (S.J.H.) C.Hoffmann@toxi.uni-wuerzburg.de.
authors.forename: C
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Bio-Imaging-Center/Rudolf-Virchow-Zentrum and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.H.); Molecular Pharmacology Laboratory, Biofarma Research Group (GI-1685), University of Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Spain (M.C.); Institute of Chemistry, University of Tartu, Tartu, Estonia (A.R.); Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University, Amsterdam, Amsterdam, The Netherlands (R.L., H.F.V.); and Cell Signalling Research Group, School of Life Sciences, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom (S.J.H.).
authors.forename: M
authors.initials: M
authors.lastname: Castro
authors.affiliation: Bio-Imaging-Center/Rudolf-Virchow-Zentrum and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.H.); Molecular Pharmacology Laboratory, Biofarma Research Group (GI-1685), University of Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Spain (M.C.); Institute of Chemistry, University of Tartu, Tartu, Estonia (A.R.); Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University, Amsterdam, Amsterdam, The Netherlands (R.L., H.F.V.); and Cell Signalling Research Group, School of Life Sciences, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom (S.J.H.).
authors.forename: A
authors.initials: A
authors.lastname: Rinken
authors.affiliation: Bio-Imaging-Center/Rudolf-Virchow-Zentrum and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.H.); Molecular Pharmacology Laboratory, Biofarma Research Group (GI-1685), University of Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Spain (M.C.); Institute of Chemistry, University of Tartu, Tartu, Estonia (A.R.); Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University, Amsterdam, Amsterdam, The Netherlands (R.L., H.F.V.); and Cell Signalling Research Group, School of Life Sciences, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom (S.J.H.).
authors.forename: R
authors.initials: R
authors.lastname: Leurs
authors.affiliation: Bio-Imaging-Center/Rudolf-Virchow-Zentrum and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.H.); Molecular Pharmacology Laboratory, Biofarma Research Group (GI-1685), University of Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Spain (M.C.); Institute of Chemistry, University of Tartu, Tartu, Estonia (A.R.); Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University, Amsterdam, Amsterdam, The Netherlands (R.L., H.F.V.); and Cell Signalling Research Group, School of Life Sciences, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom (S.J.H.).
authors.forename: S J
authors.initials: SJ
authors.lastname: Hill
authors.affiliation: Bio-Imaging-Center/Rudolf-Virchow-Zentrum and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.H.); Molecular Pharmacology Laboratory, Biofarma Research Group (GI-1685), University of Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Spain (M.C.); Institute of Chemistry, University of Tartu, Tartu, Estonia (A.R.); Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University, Amsterdam, Amsterdam, The Netherlands (R.L., H.F.V.); and Cell Signalling Research Group, School of Life Sciences, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom (S.J.H.).
authors.forename: H F
authors.initials: HF
authors.lastname: Vischer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D020349:Surface Plasmon Resonance / Q000379:methods
chemical_list: D005456:Fluorescent Dyes; D008024:Ligands; D043562:Receptors, G-Protein-Coupled