Perspective: Implications of Ligand–Receptor Binding Kinetics for Therapeutic Targeting of G Protein-Coupled Receptors

Abstract

The concept of ligand−receptor binding kinetics has been broadly applied in drug development pipelines focusing on G protein-coupled receptors (GPCRs). The ligand residence time (RT) for a receptor describes how long a ligand−receptor complex exists, and is defined as the reciprocal of the dissociation rate constant (k off ). RT has turned out to be a valuable parameter for GPCR researchers focusing on drug development as a good predictor of in vivo efficacy. The positive correlation between RT and in vivo efficacy has been established for several drugs targeting class A GPCRs (e.g., the neurokinin-1 receptor (NK 1 R), the β 2 adrenergic receptor (β 2 AR), and the muscarinic 3 receptor (M 3 R)) and for drugs targeting class B1 (e.g., the glucagon-like peptide 1 receptor (GLP-1R)). Recently, the association rate constant (k on ) has gained similar attention as another parameter affecting in vivo efficacy. In the current perspective, we address the importance of studying ligand−receptor binding kinetics for therapeutic targeting of GPCRs, with an emphasis on how binding kinetics can be altered by subtle molecular changes in the ligands and/or the receptors and how such changes affect treatment outcome. Moreover, we speculate on the impact of binding kinetic parameters for functional selectivity and sustained receptor signaling from endosomal compartments; phenomena that have gained increasing interest in attempts to improve therapeutic targeting of GPCRs. KEYWORDS: association rate constant (k on ), dissociation rate constant (k off ), residence time (RT), ligand−receptor binding kinetics, G protein-coupled receptors (GPCRs)

Development of High-Specificity Fluorescent Probes to Enable Cannabinoid Type 2 Receptor Studies in Living Cells

“…[52][53][54][55][56] In addition, time-resolved methods (TR-FRET) enable studying ligand binding kinetics, one of the key determinants of drug efficacy and safety. [57][58][59][60][61][62] Towards this end, Human Embryonic Kidney (HEK293T-Rex) cells overexpressing SNAP-tagged hCB2R were labeled with a SNAP-Lumi4-Tb FRET-donor (see SI). Laser excitation (337 nm) of this donor initiates energy transfer (FRET) to a proximal fluorescent probe acceptor.…”

Development of high-affinity agonist- and antagonist radioligands for the GLP-2 receptor - powerful tools for the study of GLP-2 pharmacology

“…Interestingly, for the first time among class B1 GPCRs, we describe the binding kinetics of a peptide agonist in comparison with a peptide antagonist and show, that the on-rate for the antagonist is significantly faster than for the agonist. Binding kinetics parameters, including k on and k off , have been highlighted to be more important in describing a ligand's in vivo efficacy and the onset of action, than the classical parameters such as K D and K I (Velden et al 2020). The slower on-rate for the agonist could reflect a more complex binding compared to the antagonist in line with expected induction of active receptor states (Zhang et al 2018).…”

“…Since ligand-receptor binding kinetics is a key determinant of ligand efficacy (Velden et al 2020), we determined the association (k on ) and dissociation (k off ) rates of both radioligands, using cell membranes stably expressing the hGLP-2R. For both ligands, the kinetic profiles were best fitted with a one-phase association and a one-phase dissociation.…”

G Protein-Coupled Receptor-Ligand Dissociation Rates and Mechanisms from τRAMD Simulations

“…Signal transduction is controlled by the binding of various orthosteric and allosteric compounds, ions and lipids to GPCRs, as well as by the ability of GPCRs to undergo structural transformations 2 . The interplay between these dynamic processes regulates signal transmission in a time-dependent manner, indicating that particular signaling profiles may be achieved through the optimization of the GPCR binding kinetic parameters of drugs 3,4,5,6,7 . The impact of the binding and unbinding kinetics on GPCR drug efficacy in vivo has been outlined in several recent reviews and is currently an area of active research 8,3,9,10 .…”

“…The interplay between these dynamic processes regulates signal transmission in a time-dependent manner, indicating that particular signaling profiles may be achieved through the optimization of the GPCR binding kinetic parameters of drugs 3,4,5,6,7 . The impact of the binding and unbinding kinetics on GPCR drug efficacy in vivo has been outlined in several recent reviews and is currently an area of active research 8,3,9,10 . Another important aspect of GPCRs is that all the members of this protein superfamily have a seven transmembrane -helix bundle structure, which makes the design of drugs with high selectivity quite challenging 11 .…”