Discovery of human TyrRS inhibitors by structure-based virtual screening, structural optimization, and bioassays

Shenzhen Huang; Xiang Wang; Guifeng Lin; Jie Cheng; Xiuli Chen; Weining Sun; Rong Xiang; Yamei Yu; Linli Li; Shengyong Yang

doi:10.1039/C9RA00458K

Discovery of human TyrRS inhibitors by structure-based virtual screening, structural optimization, and bioassays†

Shenzhen Huang,

‡^a Xiang Wang,‡^bc Guifeng Lin,^a Jie Cheng,^a Xiuli Chen,^a Weining Sun,^d Rong Xiang,^b Yamei Yu,^a Linli Li^d and Shengyong Yang

*^a

Author affiliations

* Corresponding authors

^a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
E-mail: yangsy@scu.edu.cn

^b Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China

^c Department of Chemistry, Fudan University, Shanghai 200433, China

^d Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China

Abstract

The human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS), which is well known for its essential aminoacylation function in protein synthesis, has been shown to translocate to the nucleus and protect against DNA damage caused by external stimuli. Small molecules that can fit into the active site pocket of TyrRS are thought to affect the nuclear role. The exploitation of TyrRS inhibitors has attracted attention recently. In this investigation, we adopted a structure-based virtual screening strategy and subsequent structure–activity relationship analysis to discover new TyrRS inhibitors, and identified a potent compound 5,7-dihydroxy-6,8-bis((3-hydroxyphenyl)thio)-2-phenyl-4H-chromen-4-one (compound 11, K_i = 8.8 μM). In intact HeLa cells, this compound showed a protective effect against DNA damage. Compound 11 is a good lead compound for the further development of drugs against disorders caused by DNA damage.

This article is part of the themed collection: Editors' collection: Chemical Biology

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Discovery of human TyrRS inhibitors by structure-based virtual screening, structural optimization, and bioassays†

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Discovery of human TyrRS inhibitors by structure-based virtual screening, structural optimization, and bioassays

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