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    题名: Phenylphthalazines as small-molecule inhibitors of urea transporter UT-B and their binding model
    作者: Jian-hua Ran;Min Li;Weng-Ieong Tou;Tian-luo Lei;Hong Zhou;陳語謙;Calvin Yu-Chian Chen;*;Bao-xue Yang;*
    贡献者: 生物資訊與醫學工程學系
    日期: 2016-05
    上传时间: 2016-08-08 11:17:26 (UTC+8)
    摘要: Aim:

    Urea transporters (UT) are a family of transmembrane proteins that specifically transport urea. UT inhibitors exert diuretic activity without affecting electrolyte balance. The purpose of this study was to discover novel UT inhibitors and determine the inhibition mechanism.


    The primary screening urea transporter B (UT-B) inhibitory activity was conducted in a collection of 10 000 diverse small molecules using mouse erythrocyte lysis assay. After discovering a hit with a core structure of 1-phenylamino-4-phenylphthalazin, the UT-B inhibitory activity of 160 analogs were examined with a stopped-flow light scattering assay and their structure-activity relationship (SAR) was analyzed. The inhibition mechanism was further investigated using in silico assays.


    A phenylphthalazine compound PU1424, chemically named 5-(4-((4-methoxyphenyl) amino) phthalazin-1-yl)-2-methylbenzene sulfonamide, showed potent UT-B inhibition activity, inhibited human and mouse UT-B-mediated urea transport with IC50 value of 0.02 and 0.69 μmol/L, respectively, and exerted 100% UT-B inhibition at higher concentrations. The compound PU1424 did not affect membrane urea transport in mouse erythrocytes lacking UT-B. Structure-activity analysis revealed that the analogs with methoxyl group at R4 and sulfonic amide at R2 position exhibited the highest potency inhibition activity on UT-B. Furthermore, in silico assays validated that the R4 and R2 positions of the analogs bound to the UT-B binding pocket and exerted inhibition activity on UT-B.


    The compound PU1424 is a novel inhibitor of both human and mouse UT-B with IC50 at submicromolar ranges. Its binding site is located at the So site of the UT-B structure.
    显示于类别:[生物資訊與醫學工程學系 ] 期刊論文


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