Prediction and Evaluation of Protein Farnesyltransferase Inhibition by Commercial Drugs

被引:36
作者
DeGraw, Amanda J. [2 ]
Keiser, Michael J. [1 ]
Ochocki, Joshua D. [2 ]
Shoichet, Brian K. [1 ]
Distefano, Mark D. [2 ]
机构
[1] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA
[2] Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
ALLERGIC RHINITIS; RAS FARNESYL; DISEASE; PHARMACOLOGY; ASSOCIATION; RUPATADINE; DISCOVERY; SUBSTRATE; CHEMISTRY; PEPTIDE;
D O I
10.1021/jm901613f
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The similarity ensemble approach (SEA) relates proteins based on the set-wise chemical similarity among their ligands. It can be used to rapidly search large compound databases and to build cross-target similarity maps. The emerging maps relate targets in ways that reveal relationships one might not recognize based on sequence or structural similarities alone. SEA has previously revealed cross talk between drugs acting primarily on G-protein coupled receptors (GPCRs). Here we used SEA to look for potential off-target inhibition of the enzyme protein farnesyltransferase (PFTase) by commercially available drugs. The inhibition of PFTase has profound consequences for oncogenesis, as well as a number of other diseases. In the present study, two commercial drugs, Loratadine and Miconazole, were identified as potential ligands for PFTase and subsequently confirmed as such experimentally. These results point toward the applicability of SEA for the prediction of not only GPCR GPCR drug cross talk but also GPCR enzyme and enzyme enzyme drug cross talk.
引用
收藏
页码:2464 / 2471
页数:8
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