Chemical Inhibition of Human Thymidylate Kinase and Structural Insights into the Phosphate Binding Loop and Ligand-Induced Degradation
Journal
Journal of Medicinal Chemistry
Journal Volume
59
Journal Issue
21
Pages
9906-9918
Date Issued
2016
Author(s)
Chen, Yi-Hsuan
Hsu, Hua-Yi
Yeh, Ming-Tyng
Chen, Chen-Cheng
Huang, Chang-Yu
Chung, Ying-Hsuan
WEI-CHEN KUO
Weng, Jui-Hsia
Chung, Bon-Chu
Chen, Y.-J.
Jian, Cheng-Bang
Shen, Ching-Chieh
Tai, H.-C.
Sheu, Sheh-Yi
Abstract
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.
SDGs
Publisher
American Chemical Society
Type
journal article