IR@PKUHSC  > 北京大学基础医学院  > 药理学系
学科主题基础医学
Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor
Li, Min1; Tou, Weng Ieong2; Zhou, Hong1; Li, Fei1,3; Ren, Huiwen1; Chen, Calvin Yu-Chian2,4,5,6; Yang, Baoxue1
刊名SCIENTIFIC REPORTS
2014-07-22
DOI10.1038/srep05775
4
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Multidisciplinary Sciences
研究领域[WOS]Science & Technology - Other Topics
关键词[WOS]URINE CONCENTRATING MECHANISM ; UT-B ; RAT-KIDNEY ; PROTEIN ; ERYTHROCYTES ; MICE ; LOCALIZATION ; IMPROVEMENT ; DYNAMICS ; LIGANDS
英文摘要

Urea transporter B (UT-B) is a membrane channel protein that specifically transports urea. UT-B null mouse exhibited urea selective urine concentrating ability deficiency, which suggests the potential clinical applications of the UT-B inhibitors as novel diuretics. Primary high-throughput virtual screening (HTVS) of 50000 small-molecular drug-like compounds identified 2319 hit compounds. These 2319 compounds were screened by high-throughput screening using an erythrocyte osmotic lysis assay. Based on the pharmacological data, putative UT-B binding sites were identified by structure-based drug design and validated by ligand-based and QSAR model. Additionally, UT-B structural and functional characteristics under inhibitors treated and untreated conditions were simulated by molecular dynamics (MD). As the result, we identified four classes of compounds with UT-B inhibitory activity and predicted a human UT-B model, based on which computative binding sites were identified and validated. A novel potential mechanism of UT-B inhibitory activity was discovered by comparing UT-B from different species. Results suggest residue PHE198 in rat and mouse UT-B might block the inhibitor migration pathway. Inhibitory mechanisms of UT-B inhibitors and the functions of key residues in UT-B were proposed. The binding site analysis provides a structural basis for lead identification and optimization of UT-B inhibitors.

语种英语
WOS记录号WOS:000339240800003
引用统计
被引频次:5[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/54557
专题北京大学基础医学院_药理学系
作者单位1.Hubei Univ Med, Sch Pharmaceut Sci, Shiyan 442000, Peoples R China
2.Asia Univ, Dept Biomed Informat, Taichung 41354, Taiwan
3.China Med Univ, Coll Med, Sch Med, Taichung 40402, Taiwan
4.Peking Univ, Sch Basic Med Sci, Dept Pharmacol, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
5.China Med Univ Hosp, Dept Med Res, Human Genet Ctr, Taichung, Taiwan
6.China Med Univ, Res Ctr Chinese Med & Acupuncture, Taichung 40402, Taiwan
推荐引用方式
GB/T 7714
Li, Min,Tou, Weng Ieong,Zhou, Hong,et al. Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor[J]. SCIENTIFIC REPORTS,2014,4.
APA Li, Min.,Tou, Weng Ieong.,Zhou, Hong.,Li, Fei.,Ren, Huiwen.,...&Yang, Baoxue.(2014).Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor.SCIENTIFIC REPORTS,4.
MLA Li, Min,et al."Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor".SCIENTIFIC REPORTS 4(2014).
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