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

ABSTRACT: The drug discovery and development process is greatly hampered by difficulties in translating in vitro potency to in vivo efficacy. Recent studies suggest that the long-neglected drug-target residence time parameter complements classical drug affinity parameters (K I, K d, IC50, or EC50) and is a better predictor of in vivo efficacy. Compounds with a long drug-target residence time are often more efficacious in vivo. The impact, however, of the drug-target residence time on in vivo efficacy remains controversial due to difficulties in experimentally determining the in vivo target occupancy during drug treatment. To tackle this problem, an in vivo 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 in vivo 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.

SUBMITTER: Lee KSS

PROVIDER: S-EPMC6764161 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Lee Kin Sing Stephen KSS Yang Jun J Niu Jun J Ng Connie J CJ Wagner Karen M KM Dong Hua H Kodani Sean D SD Wan Debin D Morisseau Christophe C Hammock Bruce D BD

ACS central science 20190903 9

The drug discovery and development process is greatly hampered by difficulties in translating in vitro potency to in vivo efficacy. Recent studies suggest that the long-neglected drug-target residence time parameter complements classical drug affinity parameters (K I, K d, IC50, or EC50) and is a better predictor of in vivo efficacy. Compounds with a long drug-target residence time are often more efficacious in viv ...[more]

PMID: 31572788

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

Publications

Drug-Target Residence Time Affects <i>in Vivo</i> Target Occupancy through Multiple Pathways.

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