The impact of drug-target binding kinetics on in vivo drug effects
The IMI project “Kinetics for Drug Discovery” (K4DD) aims to improve the drug discovery process by considering drug-target binding kinetics in the early phase of drug discovery.
- Elizabeth (Liesbeth) de Lange
To that end, the K4DD consortium aims to generate understanding of the determinants of binding kinetics, to develop robust assays to measure binding kinetics and to obtain a better understanding of the influence of drug-target binding kinetics on in vivo drug action.
Our focus is to understand the impact of drug-target binding kinetics to the in vivo drug effect. This implies an integrative approach to the contribution of all factors that contribute to the drug effect, namely the pharmacokinetics, target synthesis and breakdown, competition with endogenous ligands and signal transduction. To assess the influence of binding kinetics in this context, we combine existing mathematical models that describe these processes and analyse these models with respect to the role of binding kinetics.
- de Witte, W.E.A. et al. (2015) Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients. Expert Opin. Drug Discov. 11, 45–63
- de Witte, W.E.A. et al. (2016) In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant. Trends Pharmacol. Sci. 37, 831-42