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

Yaxue Zhao; Qing Wang; Qingqing Meng; Dazhong Ding; Huaiyu Yang; Guangwei Gao; Dawei Li; Weiliang Zhu; Huchen Zhou

doi:10.1016/j.bmc.2011.12.035

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

Yaxue Zhao
, Qing Wang
, Qingqing Meng
, Dazhong Ding
, Huaiyu Yang
, Guangwei Gao
, Dawei Li
, Weiliang Zhu
, Huchen Zhou^*

^*Corresponding author for this work

Shanghai Jiao Tong University
CAS - Shanghai Institute of Materia Medica

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

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.

Original language	English
Pages (from-to)	1240-1250
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	3
DOIs	https://doi.org/10.1016/j.bmc.2011.12.035
State	Published - 1 Feb 2012
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Docking
Human African trypanosomiasis
Leucyl-tRNA synthetase
Pharmacophore
Trypanosoma brucei
Virtual screening

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10.1016/j.bmc.2011.12.035

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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.",

keywords = "Docking, Human African trypanosomiasis, Leucyl-tRNA synthetase, Pharmacophore, Trypanosoma brucei, Virtual screening",

author = "Yaxue Zhao and Qing Wang and Qingqing Meng and Dazhong Ding and Huaiyu Yang and Guangwei Gao and Dawei Li and Weiliang Zhu and Huchen Zhou",

year = "2012",

month = feb,

day = "1",

doi = "10.1016/j.bmc.2011.12.035",

language = "英语",

volume = "20",

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journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

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T1 - Identification of Trypanosoma brucei leucyl-tRNA synthetase inhibitors by pharmacophore- and docking-based virtual screening and synthesis

AU - Zhao, Yaxue

AU - Wang, Qing

AU - Meng, Qingqing

AU - Ding, Dazhong

AU - Yang, Huaiyu

AU - Gao, Guangwei

AU - Li, Dawei

AU - Zhu, Weiliang

AU - Zhou, Huchen

PY - 2012/2/1

Y1 - 2012/2/1

N2 - 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.

AB - 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.

KW - Docking

KW - Human African trypanosomiasis

KW - Leucyl-tRNA synthetase

KW - Pharmacophore

KW - Trypanosoma brucei

KW - Virtual screening

UR - https://www.scopus.com/pages/publications/84862810944

U2 - 10.1016/j.bmc.2011.12.035

DO - 10.1016/j.bmc.2011.12.035

M3 - 文章

C2 - 22249121

AN - SCOPUS:84862810944

SN - 0968-0896

VL - 20

SP - 1240

EP - 1250

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 3

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

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