TY - JOUR

T1 - Perspective

T2 - Implications of Ligand-Receptor Binding Kinetics for Therapeutic Targeting of G Protein-Coupled Receptors

AU - van der Velden, Wijnand J. C.

AU - Heitman, Laura H.

AU - Rosenkilde, Mette M.

PY - 2020

Y1 - 2020

N2 - 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 beta(2) adrenergic receptor (beta(2)AR), 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.

AB - 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 beta(2) adrenergic receptor (beta(2)AR), 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.

KW - association rate constant (k(on))

KW - dissociation rate constant (k(off))

KW - residence time (RT)

KW - ligand-receptor binding kinetics

KW - G protein-coupled receptors (GPCRs)

KW - POSITIVE ALLOSTERIC MODULATORS

KW - CRYO-EM STRUCTURE

KW - RESIDENCE TIME

KW - IN-VITRO

KW - MOLECULAR-MECHANISM

KW - INSULIN-SECRETION

KW - ASSOCIATION RATE

KW - GLP-1 RECEPTOR

KW - GIP RECEPTOR

KW - DRUG-BINDING

U2 - 10.1021/acsptsci.0c00012

DO - 10.1021/acsptsci.0c00012

M3 - Journal article

C2 - 32296761

VL - 3

SP - 179

EP - 189

JO - ACS Pharmacology and Translational Science

JF - ACS Pharmacology and Translational Science

SN - 2575-9108

IS - 2

ER -