Discovery of Potent, Selective Multidrug and Toxin Extrusion Transporter 1 (MATE1, SLC47A1) Inhibitors Through Prescription Drug Profiling and Computational Modeling
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- 作者：Matthias B. Wittwer ; Arik A. Zur ; Natalia Khuri ; Yasuto Kido ; Alan Kosaka ; Xuexiang Zhang ; Kari M. Morrissey ; Andrej Sali ; Yong Huang ; Kathleen M. Giacomini
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：February 14, 2013
- 年：2013
- 卷：56
- 期：3
- 页码：781-795
- 全文大小：621K
- 年卷期：v.56,no.3(February 14, 2013)
- ISSN：1520-4804
文摘
The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug鈥揹rug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP+ uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.