THIOPURINE METHYLTRANSFERASE - STRUCTURE-ACTIVITY-RELATIONSHIPS FOR BENZOIC-ACID INHIBITORS AND THIOPHENOL SUBSTRATES
THIOPURINE METHYLTRANSFERASE - STRUCTURE-ACTIVITY-RELATIONSHIPS FOR BENZOIC-ACID INHIBITORS AND THIOPHENOL SUBSTRATES
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DOI：
10.1021/jm00153a009
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发表时间：
1986-03-01
影响因子：
7.3
通讯作者：
WEINSHILBOUM, RM
中科院分区：
文献类型：
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作者：
AMES, MM;SELASSIE, CD;WEINSHILBOUM, RM
二十七种取代苯甲酸已被研究作为部分纯化的人肾硫嘌呤甲基转移酶 (TPMT) 的抑制剂。定量构效关系 (QSAR) 分析得出以下方程：pI50 = 1.25(.+-. 0.53).pi.''3+0.73(.+-. 0.38)MR3.4+2.92(.+-. 0.39)。在此等式中，pI50 是抑制酶活性 50% 的化合物浓度的对数 (IC50)； .pi.''3是两个间位取代基中疏水性较高的一个的相对疏水性； MR3,4是苯环上两个间位取代基和对位取代基中较疏水的摩尔折射率。此外，还测试了 14 种取代苯硫酚作为酶的底物。测试的所有 14 种苯硫酚都是优异的底物，其 Km 常数 (0.8-7.8 μM) 比任何已知的 TPMT 硫代嘌呤底物低至少 2 个数量级。然而，苯硫酚底物的活性与其理化参数之间没有明显的关系。这些结果表明 TPMT 的苯甲酸抑制剂和苯硫酚底物可能与酶上的不同位点相互作用。
Twenty-seven substituted benzoic acids have been studied as inhibitors of partially purified human renal thiopurine methyltransferase (TPMT). Quantitative structure-activity relationship (QSAR) analysis resulted in the following equation: pI50 = 1.25(.+-. 0.53).pi.''3+0.73(.+-. 0.38)MR3.4+2.92(.+-. 0.39). In this equation pI50 is the -log of the concentration of compound that inhibits the enzyme activity by 50% (IC50); .pi.''3 is the relative hydrophobicity of the more hydrophobic of the two meta substituents; and MR3,4 is the molar refractivity of the more hydrophobic of the two meta substituents and of the para substituent on the phenyl ring. In addition, 14 substituted thiophenols were tested as substrates for the enzyme. All 14 thiophenols tested were excellent substrates with Km constants (0.8-7.8 .mu.M) that were at least 2 orders of magnitude lower than those of any known thiopurine substrate for TPMT. However, there was no discernible relationship between the activities of thiophenol substrates and their physicochemical parameters. These results suggest that benzoic acid inhibitors of and thiophenol substrates for TPMT may interact with different sites on the enzyme.