Perspective: Implications of Ligand-Receptor Binding Kinetics for Therapeutic Targeting of G Protein-Coupled Receptors
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | ACS Pharmacology & Translational Science |
Volume | 3 |
Issue number | 2 |
Pages (from-to) | 179-189 |
Number of pages | 11 |
ISSN | 2575-9108 |
DOIs | |
Publication status | Published - 2020 |
- association rate constant (k(on)), dissociation rate constant (k(off)), residence time (RT), ligand-receptor binding kinetics, G protein-coupled receptors (GPCRs), POSITIVE ALLOSTERIC MODULATORS, CRYO-EM STRUCTURE, RESIDENCE TIME, IN-VITRO, MOLECULAR-MECHANISM, INSULIN-SECRETION, ASSOCIATION RATE, GLP-1 RECEPTOR, GIP RECEPTOR, DRUG-BINDING
Research areas
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155193/pdf/pt0c00012.pdf
Final published version
ID: 256890806