Journal of Medicinal Chemistry p. 9906 - 9918 (2016)
Update date:2022-08-15
Topics:
Chen, Yi-Hsuan
Hsu, Hua-Yi
Yeh, Ming-Tyng
Chen, Chen-Cheng
Huang, Chang-Yu
Chung, Ying-Hsuan
Chang, Zee-Fen
Kuo, Wei-Chen
Chan, Nei-Li
Weng, Jui-Hsia
Chung, Bon-Chu
Chen, Yu-Ju
Jian, Cheng-Bang
Shen, Ching-Chieh
Tai, Hwan-Ching
Sheu, Sheh-Yi
Fang, Jim-Min
Targeting thymidylate kinase (TMPK) that catalyzes the phosphotransfer reaction for formation of dTDP from dTMP is a new strategy for anticancer treatment. This study is to understand the inhibitory mechanism of a previously identified human TMPK (hTMPK) inhibitor YMU1 (1a) by molecular docking, isothermal titration calorimetry, and photoaffinity labeling. The molecular dynamics simulation suggests that 1a prefers binding at the catalytic site of hTMPK, whereas the hTMPK inhibitors that bear pyridino[d]isothiazolone or benzo[d]isothiazolone core structure in lieu of the dimethylpyridine-fused isothiazolone moiety in 1a can have access to both the ATP-binding and catalytic sites. The binding sites of hTMPK inhibitors were validated by photoaffinity labeling and mass spectrometric studies. Taking together, 1a and its analogues stabilize the conformation of ligand-induced degradation (LID) region of hTMPK and block the catalytic site or ATP-binding site, thus attenuating the ATP binding-induced closed conformation that is required for phosphorylation of dTMP.
View MoreZhejiang Golden-Shell Pharmaceutical Co.,Ltd.
Contact:+86-576-87501888 / 87501988
Address:No.89 Zhongxing Road. Li'ao, Yuhuan, Zhejiang, China
Henan Techway Chemical Co.,Ltd.
website:http://www.techwaychem.com
Contact:+86-371-66380080
Address:No.27 Shunhe Road,
Tianjin Jiuri New Materials Co., Ltd.
Contact:+86-22-58889220
Address:C-5/6, Vison Hill, No.1 Gonghua Road, Huayuan Hi-tech Park, Tianjin, China.
Contact:0086-357-6662688
Address:Zhaocheng town, Hongtong County, Linfen City, Shanxi Province
website:http://www.orchid-chem.com
Contact:+86-571-85395792
Address:607, North Zhongshan Road, Hangzhou 310000 China
Doi:10.1055/s-0031-1289694
(2012)Doi:10.1039/c2cc31001e
(2012)Doi:10.1016/S0040-4039(00)93497-X
(1991)Doi:10.1007/BF00474011
(1991)Doi:10.1039/DT9910002643
(1991)Doi:10.1134/S1070363207090186
(2007)