7V6X

Crystal structure of HPPD complexed with Y18556

Summary for 7V6X

• Entry DOI: 10.2210/pdb7v6x/pdb
• Descriptor: 4-hydroxyphenylpyruvate dioxygenase, COBALT (II) ION, 5-methyl-3-[(2-methylphenyl)methyl]-6-[(1~{R},2~{S})-2-oxidanyl-6-oxidanylidene-cyclohexyl]carbonyl-1,2,3-benzotriazin-4-one, ... (4 entities in total)
• Functional Keywords: complex, inhibitor, oxidoreductase
• Biological source: Arabidopsis thaliana (Mouse-ear cress)
• Total number of polymer chains: 1
• Total formula weight: 46417.11

Authors

Lin, H.Y.,Yang, G.F. (deposition date: 2021-08-20, release date: 2022-08-24, Last modification date: 2024-11-13)

Primary citation

Yan, Y.C.,Wu, W.,Huang, G.Y.,Yang, W.C.,Chen, Q.,Qu, R.Y.,Lin, H.Y.,Yang, G.F.
Pharmacophore-Oriented Discovery of Novel 1,2,3-Benzotriazine-4-one Derivatives as Potent 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.
J.Agric.Food Chem., 70:6644-6657, 2022

PubMed Abstract: 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a functional protein existing in almost all aerobic organisms. In the field of agricultural chemicals, HPPD is acknowledged to be one of the crucial targets for herbicides at present due to its unique bio-function in plants. In the Auto Core Fragment Screening (ACFIS) web server, a potential HPPD inhibitor featuring 1,2,3-benzotriazine-4-one was screened out via a pharmacophore-linked fragment virtual screening (PFVS) method. Molecular simulation studies drove the process of "hit-to-lead" optimization, and a family of 1,2,3-benzotriazine-4-one derivatives was synthesized. Consequently, 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-5-methyl-3-(2-methylbenzyl)benzo[][1,2,3]triazin-4(3)-one () was identified to be the best HPPD inhibitor (IC = 36 nM) among the 1,2,3-benzotriazine-4-one derivatives, which had over 8-fold improvement of enzyme inhibition compared with the positive control mesotrione (IC = 289 nM). Crystallography information for the HPPD- complex revealed several important interactions of the ligand bound upon the target protein, i.e., the bidentate chelating interaction of the triketone motif with the metal ion of HPPD, a tight π-π stacking interaction consisting of the1,2,3-benzotriazine-4-one moiety and two benzene rings of Phe-424 and Phe-381, and the polydirectional hydrophobic contacts consisting of the -CH-benzyl group of the core scaffold and some hydrophobic residues. Furthermore, compound displayed 100% inhibition against the five species of target weeds at the tested dosage, which was comparable to the weed control of mesotrione. Collectively, the fused 1,2,3-benzotriazine-4-one-triketone hybrid is a promising chemical tool for the development of more potent HPPD inhibitors and provides a valuable lead compound for herbicide innovation.

PubMed: 35618678
DOI: 10.1021/acs.jafc.2c01507

Experimental method

X-RAY DIFFRACTION (1.8 Å)