Dynamics of ligand binding to GPCR: Residence time of melanocortins and its modulation.
Ligand binding dynamics and the concept of drug-target residence time are essential factors in the development of novel drugs. Conventional ligand binding assays, which usually collect end-point data, do not provide abundant information regarding the ligand binding kinetics. Therefore, novel methods that allow on-line monitoring of ligand binding processes have to be developed and implemented for drug discovery studies. In this study, we provide a short overview of novel possibilities to characterize ligand binding dynamics to different G protein-coupled receptors (GPCRs). Special attention has been paid to the ligand binding to melanocortin 4 receptors and to the development of a fluorescence anisotropy-based assay system using receptors in budded baculovirus particles. It has been shown that ligand binding to melanocortin 4 receptors occurs to tandemly arranged interconnecting ligand binding sites and that the conventional equilibrium usually cannot be achieved in this system. Therefore, the apparent potencies of the same ligand may differ by up to four orders of magnitude, depending on the experimental conditions and the reporter ligand used.
Institute of Chemistry, University of Tartu, Estonia. Electronic address: ago.rinken@ut.ee.
Ago
A
Rinken
Institute of Chemistry, University of Tartu, Estonia.
Santa
S
Veiksina
Institute of Chemistry, University of Tartu, Estonia.
Sergei
S
Kopanchuk
D001665:Binding Sites / Q000502:physiology; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D007700:Kinetics; D008024:Ligands; D053486:Melanocortins / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D008024:Ligands; D053486:Melanocortins; D044105:Receptor, Melanocortin, Type 4; D043562:Receptors, G-Protein-Coupled
Binding model; Budded baculoviruses; Fluorescence anisotropy; G-protein-coupled receptors; Melanocortin 4 receptor; Residence time