Kinetic Profile of Neuropeptide–Receptor Interactions

Drug–target binding kinetics can be described by the association and dissociation rate of a drug to and from its target. Increasing evidence from literature is providing proof of the importance of drug–target binding kinetics in drug discovery. The majority of drugs achieve their mechanism of action by competing with endogenous ligands. However, drug discovery predominantly focusses on the drug while the pharmacological parameters of the target and endogenous ligands are rarely taken into account. Binding kinetics, internalization kinetics and release rate (i.e., kinetic profile) of exemplary neuropeptides and their receptors are extremely diverse. Insights into the kinetic profile of the target and endogenous ligands could improve the understanding of the desired drug–target binding kinetics. Currently, drug discovery focusses only on quantifying pharmacological parameters, sometimes including binding kinetics, of drug candidates. For a complete understanding of a drug's desired binding kinetics, the kinetics of both the target and its endogenous ligands should be considered. This is because the release and binding kinetics of endogenous ligands in addition to receptor internalization rates are significant contributors to drug–target interactions. Here, we discuss the kinetic profile of three neuropeptides and their receptors; gonadotropin-releasing hormone receptor (GnRHR), neuropeptide Y receptors, and corticotropin-releasing factor receptor 1 (CRF1R). These three examples provide new insights into the importance of kinetic profiles which could improve the understanding of desired drug–target binding kinetics and advance drug discovery for various neurological and psychiatric illnesses. Currently, drug discovery focusses only on quantifying pharmacological parameters, sometimes including binding kinetics, of drug candidates. For a complete understanding of a drug's desired binding kinetics, the kinetics of both the target and its endogenous ligands should be considered. This is because the release and binding kinetics of endogenous ligands in addition to receptor internalization rates are significant contributors to drug–target interactions. Here, we discuss the kinetic profile of three neuropeptides and their receptors; gonadotropin-releasing hormone receptor (GnRHR), neuropeptide Y receptors, and corticotropin-releasing factor receptor 1 (CRF1R). These three examples provide new insights into the importance of kinetic profiles which could improve the understanding of desired drug–target binding kinetics and advance drug discovery for various neurological and psychiatric illnesses. large cell-membrane-bound receptor family comprised of seven transmembrane α helices. Each receptor has an extracellular N-terminal domain and intracellular C terminus, and upon receptor activation (i.e., by an agonist), a G protein couples to the intracellular domain of the receptor. a measure of a ligand's affinity for its target, a concentration at which 50% of the target receptors is bound with the ligand. association rate constant, a concentration-dependent rate at which a ligand binds to its target. dissociation rate constant, a concentration-independent rate at which a ligand dissociates from its target. a measure of the lifetime of a ligand–receptor complex, which is the reciprocal of the dissociation rate (1/koff). receptor desensitization occurs most often upon continuous agonist stimulation, causing reduced receptor activity through phosphorylation. Once a receptor is desensitized, it can be internalized and transported from the plasma membrane into the cell. It can then be degraded in lysosomes or be recycled back to the plasma membrane. Hence, desensitization and internalization are involved in the duration of cellular responses.