1 research outputs found
Chemical Inhibition of Human Thymidylate Kinase and Structural Insights into the Phosphate Binding Loop and Ligand-Induced Degradation
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 (<b>1a</b>) by molecular docking, isothermal titration calorimetry, and photoaffinity
labeling. The molecular dynamics simulation suggests that <b>1a</b> prefers binding at the catalytic site of hTMPK, whereas the hTMPK
inhibitors that bear pyridino[<i>d</i>]isothiazolone or
benzo[<i>d</i>]isothiazolone core structure in lieu of the
dimethylpyridine-fused isothiazolone moiety in <b>1a</b> 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, <b>1a</b> 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