4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target.
The molecular mechanism for 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) inhibition by nitisinone, a recently approved new drug for the treatment of hereditary tyrosinemia type I, has been satisfactorily explained by its action as an analogue to the substrate 4-hydroxyphenylpyruvate. In addition, a novel induced conformationally restricted 4-HPPD inhibitor, diketonitrile, which serves as a nonclassical bioisostere for rigid cyclic 1,3-diketone derivatives, has been introduced. Further application of the molecular mode of action of nitisinone in rational design of potential inhibitors for alpha-ketoglutarate-coupled dioxygenases is discussed.
Yang
Ding-Yah
DY
Department of Chemistry, Tunghai University, Taichung, Taiwan. yang@mail.thu.edu.tw
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D003512:Cyclohexanones / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000378:metabolism; D005544:Forecasting; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009570:Nitriles / Q000378:metabolism; D009579:Nitrobenzoates / Q000378:metabolism / Q000494:pharmacology; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000378:metabolism; D020176:Tyrosinemias / Q000188:drug therapy
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D009570:Nitriles; D009579:Nitrobenzoates; D013450:Sulfones; C486641:diketonitrile; D010105:Oxygenases; D015111:4-Hydroxyphenylpyruvate Dioxygenase; C077073:nitisinone