Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Belo Horizonte, MG, CEP 31270-901, Brazil.
Int J Biol Macromol. 2010 Jun;46(5):502-11. doi: 10.1016/j.ijbiomac.2010.03.006. Epub 2010 Mar 29.
Bovine trypsin is a model system for the serine protease class of enzymes, which is an important target for contemporary medicinal chemistry. Some structural and thermodynamic reports are available on its interaction with benzamidine-based compounds but no structural information is available so far on its binding modes to the active principles of the trypanocidal drugs Pentacarinate (pentamidine) and Berenil (diminazene). The crystallographic structures of bovine beta-trypsin in complex with the ligands were determined to a resolution of 1.57 A (diminazene) and 1.70 A (diminazene and pentamidine). The second benzamidine moieties in these inhibitors are bound to the enzyme in different hot spots and only few hydrogen bonds mediate these interactions. Thermodynamic parameters for the association of pentamidine with beta-trypsin reveal that this inhibitor has about 1.3-fold lower affinity than diminazene. Moreover its binding mode resembles other benzamidine-based compounds that assess the aryl binding pocket of the enzyme; however, with almost 2.5-fold higher affinity. This is the first structural evidence of the binding of Berenil and Pentacarinate active principles trypanocidal drugs to serine proteases.
牛胰蛋白酶是丝氨酸蛋白酶类酶的模型系统，是当代药物化学的重要靶点。已经有一些关于其与苯甲脒类化合物相互作用的结构和热力学报告，但迄今为止，关于其与杀锥虫药物戊烷脒（戊脒）和贝伦利（二甲嘧啶）的活性成分结合模式的结构信息尚不清楚。牛β-胰蛋白酶与配体的复合物的晶体结构已被确定到 1.57 A（二甲嘧啶）和 1.70 A（二甲嘧啶和戊脒）的分辨率。这些抑制剂中的第二个苯甲脒部分以不同的热点结合到酶上，只有少数氢键介导这些相互作用。戊脒与β-胰蛋白酶结合的热力学参数表明，该抑制剂的亲和力比二甲嘧啶低约 1.3 倍。此外，它的结合模式类似于其他评估酶芳基结合口袋的苯甲脒类化合物；然而，其亲和力高 2.5 倍。这是贝伦利和戊烷脒杀锥虫药物活性成分与丝氨酸蛋白酶结合的第一个结构证据。
