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

The drug discovery and development process is greatly hampered by difficulties in translating potency to efficacy. Recent studies suggest that the long-neglected drug-target residence time parameter complements classical drug affinity parameters ( , , IC, or EC) and is a better predictor of efficacy. Compounds with a long drug-target residence time are often more efficacious . The impact, however, of the drug-target residence time on efficacy remains controversial due to difficulties in experimentally determining the target occupancy during drug treatment. To tackle this problem, an displacement assay was developed using soluble epoxide hydrolase as a biological model. In this report, we experimentally demonstrated that drug-target residence time affects the duration of drug-target binding. In addition, the drug-target residence time plays an important role in modulating the rate of drug metabolism which also affects the efficacy of the drug.