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Title: B-Triketone Inhibitors of Plant p-Hydroxyphenylpyruvate Dioxygenase: Modeling and Comparative Molecular Field Analysis of Their Interactions

Author
item Dayan, Franck
item SINGH, NIDHI - UNIVERSITY OF MISSISSIPPI
item MCCURDY, CHRISTOPHER - UNIVERSITY OF MISSISSIPPI
item GODFREY, COLETTE - UNIVERSITY OF OTAGO
item LARSEN, LESLEY - UNIVERSITY OF OTAGO
item WEAVERS, REX - UNIVERSITY OF OTAGO
item VAN KLINK, JOHN - UNIVERSITY OF OTAGO
item PERRY, NIGEL - UNIVERSITY OF OTAGO

Submitted to: Journal of Agricultural and Food Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/4/2009
Publication Date: 5/12/2009
Citation: Dayan, F.E., Singh, N., Mccurdy, C., Godfrey, C., Larsen, L., Weavers, R.T., Van Klink, J., Perry, N. 2009. B-Triketone Inhibitors of Plant p-Hydroxyphenylpyruvate Dioxygenase: Modeling and Comparative Molecular Field Analysis of Their Interactions. Journal of Agricultural and Food Chemistry. 57:5194-5200.

Interpretive Summary: Weed control relies primarily on the use of synthetic herbicides. However, concerns over their potential impact on the environment and health necessitate the development of alternative and safer weed management tools. Natural herbicides present themselves as a potential bridge between traditional and organic agriculture. Natural products belonging to the triketone class inhibit p-hydroxyphenylpyruvate dioxygenase (HPPD) that is important for the biosynthesis of some plant pigments. This study reports the biological activity of a series of natural triketone herbicides (e.g., flavesone, grandiflorone and leptospermone) and several analogues against HPPD. Computer modeling methods such as conformational molecular field analysis and hydropathic interaction were used to analyze the data. This work provided a structure-activity relationship between the inhibitors and their potency against HPPD.

Technical Abstract: Weed control relies primarily on the use of synthetic herbicides. However, concerns over their potential impact on the environment and health necessitate the development of alternative and safer weed management tools. Natural herbicides present themselves as a potential bridge between traditional and organic agriculture. p-Hydroxyphenylpyruvate dioxygenase (HPPD) is a key enzyme in the biosynthesis of prenyl quinones. Inhibition of HPPD reduces plastoquinone levels and has deleterious effects on carotenoid synthesis and the photosynthetic apparatus. This enzyme is the target site of ß-triketone herbicides (e.g., sulcotrione and mesotrione). Dose-response curves of a set of natural ß-triketones (e.g., flavesone, grandiflorone and leptospermone) and several analogues against purified heterologously expressed A. thaliana HPPD were obtained. The steric and electrostatic contributions were determined using conformational molecular field analysis (CoMFA) and the hydrophobic contribution was analyzed with hydropathic interaction (HINT). Bulky substituents on the triketone ring structure reduced the overall inhibitory activity of the compounds whereas increase in the aliphatic tail improved the activity of the compounds up to a point. Modeling of the binding of the triketones to HPPD and computational analysis of the catalytic domain of HPPD provided a structural basis to explain the structure-activity relationship revealed by CoMFA and HINT. Briefly, the presence of these side-chains caused the volume of the inhibitors to exceed the space available in the catalytic domain centered on the Fe2+ metal ion. On the other hand, a lipophilic domain proximate to the catalytic site appears to stabilize compounds with hydrophobic tails.