6M6D

Structure of HPPD complexed with a synthesized inhibitor

Summary for 6M6D

• Entry DOI: 10.2210/pdb6m6d/pdb
• Descriptor: 4-hydroxyphenylpyruvate dioxygenase, COBALT (II) ION, 1,5-dimethyl-6-(2-oxidanyl-6-oxidanylidene-cyclohexen-1-yl)carbonyl-3-(3-trimethylsilylprop-2-ynyl)quinazoline-2,4-dione, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, oxidoreductase
• Biological source: Arabidopsis thaliana (Mouse-ear cress)
• Total number of polymer chains: 1
• Total formula weight: 49371.31

Authors

Lin, H.-Y.,Yang, W.-C.,Yang, G.-F. (deposition date: 2020-03-14, release date: 2021-03-10, Last modification date: 2024-11-13)

Primary citation

Qu, R.Y.,Nan, J.X.,Yan, Y.C.,Chen, Q.,Ndikuryayo, F.,Wei, X.F.,Yang, W.C.,Lin, H.Y.,Yang, G.F.
Structure-Guided Discovery of Silicon-Containing Subnanomolar Inhibitor of Hydroxyphenylpyruvate Dioxygenase as a Potential Herbicide.
J.Agric.Food Chem., 69:459-473, 2021

PubMed Abstract: 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been recognized as one of the most promising targets in the field of herbicide innovation considering the severity of weed resistance currently. In a persistent effort to develop effective HPPD-inhibiting herbicides, a structure-guided strategy was carried out to perform the structural optimization for triketone-quinazoline-2,4-diones, a novel HPPD inhibitor scaffold first discovered in our lab. Herein, starting from the crystal structure of ()HPPD complexed with 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(-tolyl)quinazoline-2,4(1,3)-dione (), three subseries of quinazoline-2,4-dione derivatives were designed and prepared by optimizing the hydrophobic interactions between the side chain of the core structure at the R position and the hydrophobic pocket at the active site entrance of HPPD. 6-(2-Hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(3-(trimethylsilyl)prop-2-yn-1-yl)quinazoline-2,4(1,3)-dione () with the best inhibitory activity against HPPD was identified to be the first subnanomolar-range HPPD inhibitor ( = 0.86 nM), which significantly outperformed that of the lead compound ( = 8.2 nM). Further determination of the crystal structure of HPPD in complex with compound (1.85 Å) and the binding energy calculation provided a molecular basis for the understanding of its high efficiency. Additionally, the greenhouse assay indicated that 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-propylquinazoline-2,4(1,3)-dione () and compound showed acceptable crop safety against peanut and good herbicidal activity with a broad spectrum. Moreover, compound also showed superior selectivity for wheat at the dosage of 120 g ai/ha and favorable herbicidal efficacy toward the gramineous weeds at the dosage of as low as 30 g ai/ha. We believe that compounds and have promising prospects as new herbicide candidates for wheat and peanut fields.

PubMed: 33395281
DOI: 10.1021/acs.jafc.0c03844

Experimental method

X-RAY DIFFRACTION (1.842 Å)