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

• Published in: ACS pharmacology & translational science 2020-04, Vol.3 (2), p.179-189
• Main Authors: van der Velden, Wijnand J. C, Heitman, Laura H, Rosenkilde, Mette M
• Format: Article
• Language: English
• ISSN: 2575-9108; 2575-9108
• DOI: 10.1021/acsptsci.0c00012

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 (NK1R), the β2 adrenergic receptor (β2AR), and the muscarinic 3 receptor (M3R)) 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.