Identification of Trypanosoma brucei leucyl-tRNA synthetase inhibitors by pharmacophore- and docking-based virtual screening and synthesis

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• 作者：Yaxue Zhao^a ; ^&dagger ; ; Qing Wang^a ; ^&dagger ; ; Qingqing Meng^a ; Dazhong Ding^a ; Huaiyu Yang^b ; Guangwei Gao^a ; Dawei Li^a ; Weiliang Zhu^b ; Huchen Zhou^a ; ^{hczhou@sjtu.edu.cn}
• 关键词：Human African trypanosomiasis ; Trypanosoma brucei ; Leucyl-tRNA synthetase ; Virtual screening ; Pharmacophore ; Docking
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 February, 2012
• 年：2012
• 卷：20
• 期：3
• 页码：1240-1250
• 全文大小：2245 K

文摘

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 R¹, R² and R³ were synthesized and their SAR was discussed.