From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action.

ABSTRACT: An important question in drug discovery is how to overcome the significant challenge of high drug attrition rates due to lack of efficacy and safety. A missing link in the understanding of determinants for drug efficacy is the relation between drug-target binding kinetics and signal transduction, particularly in the physiological context of (multiple) endogenous ligands. We hypothesized that the kinetic binding parameters of both drug and endogenous ligand play a crucial role in determining cellular responses, using the NK1 receptor as a model system. We demonstrated that the binding kinetics of both antagonists (DFA and aprepitant) and endogenous agonists (NKA and SP) have significantly different effects on signal transduction profiles, i.e. potency values, in vitro efficacy values and on

SUBMITTER: Nederpelt I 

PROVIDER: S-EPMC5658448 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature