How can treating neurological disease overcome challenges like the synthesis of small molecule agents that penetrate the blood-brain barrier, in order to sustain target engagement at low drug concentration?
Time-dependent target occupancy in the non-equilibrium environment of the human body is a function of both the thermodynamics and kinetics of drug-target interactions. However, often only thermodynamic parameters such as IC50 values are used for selecting and optimizing drug leads. Significantly, the rate of drug-target complex dissociation can be slower than the time scale of in vivo drug elimination, leading to sustained target occupancy at low drug concentration, enabling dosing frequency and exposure to be reduced and thus improving the therapeutic window.
Join Peter Tonge, Professor of the Center for Advanced Study of Drug Action at Stony Brook University, as he discusses the factors that affect the translation of sustained occupancy to prolonged drug activity such as target vulnerability and the rate of target turnover which in turn impact the potential benefits of kinetic selectivity.
What You Will Learn
- Selectivity has both thermodynamic and kinetic components, however most programs only focus on thermodynamic selectivity
- Kinetic selectivity can be used to widen the therapeutic window even in the absence of thermodynamic selectivity; however, the utility of kinetic selectivity depends on factors such as drug PK and target vulnerability
- Target vulnerability functions can be determined by directly correlating target occupancy and drug effect or using PK/PD models that integrate drug-target kinetics into predictions of drug activity
- Drug–Target Kinetics in Drug Discovery—Open access article in ACS Chemical Neuroscience by Peter Tonge
- Quantifying the Interactions between Biomolecules: Guidelines for Assay Design and Data Analysis—Article in ACS Infectious Diseases by Peter Tonge
The Fine Print
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