School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
Bioorg Med Chem. 2012 Feb 1;20(3):1240-50. doi: 10.1016/j.bmc.2011.12.035. Epub 2011 Dec 30.
Human African trypanosomiasis (HAT), caused by the protozoan parasite Trypanosoma brucei, is a neglected fatal disease. Leucyl-tRNA synthetase (LeuRS), which has been successfully applied in the development of antifungal agent, represents a potential antiprotozoal drug target. In this study, a 3D model of T. brucei LeuRS (TbLeuRS) synthetic active site was constructed and subjected to virtual screening using a combination of pharmacophore- and docking-based methods. A new 2-pyrrolinone scaffold was discovered and the structure-activity relationship (SAR) studies aided by the docking model and organic synthesis were carried out. Compounds with various substituents on R(1), R(2) and R(3) were synthesized and their SAR was discussed.
人类非洲锥虫病（HAT）由原生动物寄生虫布氏锥虫引起，是一种被忽视的致命疾病。亮氨酰-tRNA 合成酶（LeuRS）已成功应用于抗真菌药物的开发，代表了一种潜在的抗原生动物药物靶点。在这项研究中，构建了布氏锥虫亮氨酰-tRNA 合成酶（TbLeuRS）合成活性位点的 3D 模型，并结合基于药效团和对接的方法进行虚拟筛选。发现了一种新的 2-吡咯烷酮骨架，并通过对接模型和有机合成进行了结构-活性关系（SAR）研究。合成了具有不同取代基的 R(1)、R(2)和 R(3)的化合物，并讨论了它们的 SAR。
