title: Identification of Trypanosoma brucei leucyl-tRNA synthetase inhibitors by pharmacophore- and docking-based virtual screening and synthesis.
abstract: 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.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yaxue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Meng
authors.forename: Dazhong
authors.initials: D
authors.lastname: Ding
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.forename: Guangwei
authors.initials: G
authors.lastname: Gao
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Huchen
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D007935:Leucine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D007935:Leucine-tRNA Ligase