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学科主题: 基础医学
题名:
Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor
作者: 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
发表日期: 2014-07-22
DOI: 10.1038/srep05775
卷: 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
所属项目编号: 31200869 ; 81261160507 ; 81330074 ; 81170632 ; 2012DFA11070 ; NSC102-2325-B039-001 ; NSC102-2221-E-468-027- ; ASIA100-CMU-2 ; ASIA101-CMU-2 ; 102-Asia-07 ; DMR-103-058 ; DMR-103-001 ; DMR-103-096 ; DOH102-TD-B-111-004 ; MOHW103-TD-B-111-03
项目资助者: National Natural Science Foundation of China ; 111 Project ; International Science &amp ; Technology Cooperation Program of China ; National Science Council of Taiwan ; Asia University ; China Medical University Hospital ; Taiwan Department of Health Clinical Trial and Research Center of Excellence ; Taiwan Department of Health Cancer Research Center of Excellence ; CMU under the Ministry of Education, Taiwan
WOS记录号: WOS:000339240800003
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/54557
Appears in Collections:基础医学院_药理学系_期刊论文

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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

Recommended Citation:
Li, Min,Tou, Weng Ieong,Zhou, Hong,et al. Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor[J]. SCIENTIFIC REPORTS,2014,4.
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