Drug-Target Residence Time Affects in Vivo Target Occupancy through Multiple Pathways

Area of Science:

• Pharmacology
• Drug Discovery
• Biochemistry

Background:

• Translating in vitro drug potency to in vivo efficacy is a major challenge in drug discovery.
• Drug-target residence time is emerging as a critical parameter, potentially outperforming traditional affinity measures (e.g., Kd, IC50) in predicting in vivo outcomes.
• The precise influence of drug-target residence time on in vivo efficacy remains debated due to challenges in measuring in vivo target occupancy.

Purpose of the Study:

• To experimentally investigate the impact of drug-target residence time on in vivo drug-target binding duration.
• To explore the role of drug-target residence time in modulating drug metabolism and its subsequent effect on drug efficacy.
• To develop and validate an in vivo displacement assay for studying drug-target interactions.

Main Methods:

• Development of an in vivo displacement assay utilizing soluble epoxide hydrolase as a model system.
• Experimental determination of drug-target binding duration in vivo.
• Assessment of the influence of drug-target residence time on drug metabolism rates.

Main Results:

• Demonstrated that drug-target residence time directly affects the duration of in vivo drug-target binding.
• Established a significant role for drug-target residence time in modulating the rate of drug metabolism.
• Provided experimental evidence linking drug-target residence time to in vivo drug efficacy.

Conclusions:

• Drug-target residence time is a key determinant of in vivo drug action, influencing both binding persistence and metabolic clearance.
• The developed in vivo assay offers a valuable tool for assessing drug-target interactions and predicting in vivo efficacy.
• Understanding drug-target residence time is crucial for advancing drug discovery and development, improving the translation from in vitro to in vivo results.