Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor

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题名:	Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor
作者:	Li, Min;Li, Min;Weng Ieong, T;Tou, Weng Ieong;Zhou, Hong;Zhou, Hong;Li, Fei;Li, Fei;Ren, Huiwen;Ren, Huiwen;陳語謙*;Yang, Baoxue;Yang, Baoxue
贡献者:	生物與醫學資訊學系
日期:	2015-01
上传时间:	2015-03-11 01:24:29 (UTC+0)
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.
關聯:	Scientific Reports
显示于类别:	[生物資訊與醫學工程學系 ] 期刊論文

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