Assay Development and Screening
Since the drug-target residence time concept was first proposed more than 10 years ago, it has received much attention across drug discovery research. The central principle is that rates of drug−target complex formation (kon) and breakdown (koff) describe target engagement in open systems and that target occupancy is better predicted by kinetic (kon, koff) rather than thermodynamic (IC50, Kd) parameters in the dynamic in vivo setting. Consequently, the incorporation of binding kinetics into PK-PD models is proposed to lead to better prediction of drug efficacy. A large number of marketed drugs are characterized by long residence times, often equating with extreme potency of the binding interaction. This can confound accurate equilibrium potency measurements through both the length of time needed to reach equilibrium and tight binding limitations. Kinetic measurements are not constrained by these limitations, and can therefore offer a more practical and accurate measure of intrinsic potency. However, historical methods for determining binding kinetics are of low to medium throughput and limited to certain target classes. Recent advances in plate reader technology and the emergence of new methodologies have enabled the development and prosecution of higher throughput screens that have enabled real time measurement of on rates, off rates, and affinity.
Multidimensional approaches to determining mechanism of action at different points across early drug discovery from hit validation to candidate selection will be presented. These case studies will focus on data from complementary biochemical and cellular systems, generated using a variety of well established technologies and emerging next wave methods. Opportunities to profoundly impact drug discovery through the value of decision-making combined with an ability to effectively reduce attrition at each stage will be critical in defining future successes as an industry. Improving our understanding of both on and off-target kinetics that underpin potency will be an important component in achieving this goal.