posted on 2023-01-04, 21:12authored byJin Dong, Jiangqing Dong, Xin-He Yu, Yao-Chao Yan, Jia-Xu Nan, Bao-Qin Ye, Wen-Chao Yang, Hong-Yan Lin, Guang-Fu Yang
High-potency 4-hydroxyphenylpyruvate dioxygenase (HPPD)
inhibitors
are usually featured by time-dependent inhibition. However, the molecular
mechanism underlying time-dependent inhibition by HPPD inhibitors
has not been fully elucidated. Here, based on the determination of
the HPPD binding mode of natural products, the π–π
sandwich stacking interaction was found to be a critical element determining
time-dependent inhibition. This result implied that, for the time-dependent
inhibitors, strengthening the π–π sandwich stacking
interaction might improve their inhibitory efficacy. Consequently,
modification with one methyl group on the bicyclic ring of quinazolindione
inhibitors was achieved, thereby strengthening the stacking interaction
and significantly improving the inhibitory efficacy. Further introduction
of bulkier hydrophobic substituents with higher flexibility resulted
in a series of HPPD inhibitors with outstanding subnanomolar potency.
Exploration of the time-dependent inhibition mechanism and molecular
design based on the exploration results are very successful cases
of structure-based rational design and provide a guiding reference
for future development of HPPD inhibitors.