期刊
ACS CENTRAL SCIENCE
卷 5, 期 9, 页码 1614-1624出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.9b00770
关键词
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资金
- National Institute of Environmental Health Sciences (NIEHS) [R01 ES002710, R35 ES030443, R00 ES024806]
- NIEHS Superfund Research Program [P42 ES004699]
- National Science Foundation [DMS-1761320]
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.
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