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.

Homogeneous, Real-Time NanoBRET Binding Assays for the Histamine H3 and H4 Receptors on Living Cells

“…Residence time (RT) indicates how long a ligand stays bound to its receptor (Copeland et al, 2006;Hoffmann et al, 2015;Copeland, 2016) and was calculated using eq. 4:…”

The constitutive activity of melanocortin‐4 receptors in cAMP pathway is allosterically modulated by zinc and copper ions

“…The kinetic studies of ligand binding to GPCRs have become considerably easier after the implementation of novel fluorescence‐based methods, which allow the monitoring of the process in real‐time without the need to separate free and bound ligands (Hoffmann et al, ). A fluorescence anisotropy (FA)‐based assay has been successfully applied in kinetic studies of ligand binding to MC 4 R (Veiksina et al, ).…”

Molecular Pharmacology ofδ-Opioid Receptors

“…Nonetheless, even if kinetically determined, differences in agonist-induced responses and distinct susceptibility to antagonists could still be exploited to generate DOPr compounds with "kinetic functional selectivity" (Hoffmann et al, 2015), an avenue that might be worth exploring.…”