Department of Medicine, University of Alabama, Birmingham, Birmingham, AL 35294, USA.
Bioorg Med Chem. 2010 Jun 1;18(11):4056-66. doi: 10.1016/j.bmc.2010.04.020. Epub 2010 Apr 9.
Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas' disease. We have undertaken a detailed structure-activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme:cofactor:inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme-ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60-70% of the total binding energy is contributed by the 2,4-diaminoquinazoline scaffold.
寄生虫克氏锥虫（T. cruzi）的二氢叶酸还原酶（DHFR）是开发治疗恰加斯病药物的潜在靶标。我们对该酶进行了详细的结构-活性研究。我们在此报告了六种强效寄生虫酶抑制剂的合成和表征。每种化合物的抑制活性均针对 T. cruzi 和人 DHFR 进行了测定。这些化合物之一，乙基 4-（5-[(2,4-二氨基-6-喹唑啉基)甲基]氨基-2-甲氧基苯氧基）丁酸盐（6b）与克氏锥虫的双功能二氢叶酸还原酶-胸苷酸合酶酶共结晶，并确定了三元酶：辅因子：抑制剂复合物的晶体结构。分子对接用于分析所有抑制剂与 T. cruzi DHFR 和人 DHFR 的潜在相互作用。根据酶-配体相互作用讨论了这些化合物的抑制活性。基于实验或对接的结合模式计算了每个抑制剂对各自酶的结合亲和力。估计总结合能的 60-70％由 2,4-二氨基喹唑啉支架贡献。
