Combination of Virtual Screening Protocol by in Silico toward the Discovery of Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Frontiers in Chemistry
Ying FuFei Ye

Abstract

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a potent new bleaching herbicide target. Therefore, in silico structure-based virtual screening was performed in order to speed up the identification of promising HPPD inhibitors. In this study, an integrated virtual screening protocol by combining 3D-pharmacophore model, molecular docking and molecular dynamics (MD) simulation was established to find novel HPPD inhibitors from four commercial databases. 3D-pharmacophore Hypo1 model was applied to efficiently narrow potential hits. The hit compounds were subsequently submitted to molecular docking studies, showing four compounds as potent inhibitor with the mechanism of the Fe(II) coordination and interaction with Phe360, Phe403, and Phe398. MD result demonstrated that nonpolar term of compound 3881 made great contributions to binding affinities. It showed an IC50 being 2.49 μM against AtHPPD in vitro. The results provided useful information for developing novel HPPD inhibitors, leading to further understanding of the interaction mechanism of HPPD inhibitors.

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Citations

Mar 15, 2019·Pest Management Science·Carla Díaz-TielasStephen O Duke
Aug 17, 2019·Current Topics in Medicinal Chemistry·Sheisi F L da Silva RochaCarlos M R Sant'Anna
May 2, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yankun ChenYanling Zhang
Apr 12, 2021·Pesticide Biochemistry and Physiology·Ying FuFei Ye
Jan 19, 2022·Journal of Agricultural and Food Chemistry·Li-Xia ZhaoFei Ye

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Software Mentioned

PBSA
Sander
MM
Chembridge
Gaussian03
SYBYL
LEaP
Amber
Antechamber
CDOCKER

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