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4 Hydroxyphenylpyruvate Dioxygenase

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Guang-fu Yang – One of the best experts on this subject based on the ideXlab platform.

  • Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4Hydroxyphenylpyruvate Dioxygenase Inhibitors.
    Journal of agricultural and food chemistry, 2020
    Co-Authors: Qiong Chen, Hong-yan Lin, Ge-fei Hao, Wen-chao Yang, Guang-fu Yang
    Abstract:

    4Hydroxyphenylpyruvate Dioxygenase (HPPD, EC 1.13.11.27) has been identified as one of the most significant targets in herbicide discovery for resistant weed control. In a continuing effort to dis…

  • Pyrazole–Isoindoline-1,3-dione Hybrid: A Promising Scaffold for 4Hydroxyphenylpyruvate Dioxygenase Inhibitors
    Journal of agricultural and food chemistry, 2019
    Co-Authors: Jin Dong, Hong-yan Lin, Ge-fei Hao, Wen-chao Yang, Qiong Chen, Meng-yao Wang, Bai-feng Zheng, Guang-fu Yang
    Abstract:

    The discovery of 4Hydroxyphenylpyruvate Dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 μM to over 1 μM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4– carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 A. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.

  • pyrazole isoindoline 1 3 dione hybrid a promising scaffold for 4 Hydroxyphenylpyruvate Dioxygenase inhibitors
    Journal of Agricultural and Food Chemistry, 2019
    Co-Authors: Jin Dong, Hong-yan Lin, Guang-fu Yang, Ge-fei Hao, Wen-chao Yang, Qiong Chen, Meng-yao Wang, Bai-feng Zheng
    Abstract:

    The discovery of 4Hydroxyphenylpyruvate Dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 μM to over 1 μM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4– carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 A. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.

Ding-yah Yang – One of the best experts on this subject based on the ideXlab platform.

  • Acylcyclohexanedione derivatives as potential in vivo sequential inhibitors of 4Hydroxyphenylpyruvate Dioxygenase and GA20 3β-hydroxylase
    Bioorganic & medicinal chemistry letters, 2003
    Co-Authors: Jian-lin Huang, Hun-ge Liu, Ding-yah Yang
    Abstract:

    Abstract Acylcyclohexanedione derivatives have been designed, synthesized, and evaluated for in vitro inhibition activity against the enzyme 4Hydroxyphenylpyruvate Dioxygenase (4-HPPD). The biological data demonstrated that 7 is a potent inhibitor of 4-HPPD with an IC50 value of 40 nM. After metabolism, compound 7 has the potential to become a potent inhibitor of a second enzyme, GA20 3β-hydroxylase.

  • 4Hydroxyphenylpyruvate Dioxygenase as a drug discovery target.
    Drug news & perspectives, 2003
    Co-Authors: Ding-yah Yang
    Abstract:

    The molecular mechanism for 4Hydroxyphenylpyruvate 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 4Hydroxyphenylpyruvate. 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.

  • 3D-QSAR studies on 4Hydroxyphenylpyruvate Dioxygenase inhibitors by comparative molecular field analysis (CoMFA).
    Bioorganic & medicinal chemistry letters, 2002
    Co-Authors: Meilan Huang, Ding-yah Yang, Zhicai Shang, Jian-wei Zou
    Abstract:

    A comparative molecular field analysis (CoMFA) of alkanoic acid 3-oxo-cyclohex-1-enyl ester and 2-acylcyclohexane-1,3-dione derivatives of 4Hydroxyphenylpyruvate Dioxygenase inhibitors has been performed to determine the factors required for the activity of these compounds. The substrate’s conformation abstracted from dynamic modeling of the enzyme-substrate complex was used to build the initial structures of the inhibitors. Satisfactory results were obtained after an all-space searching procedure, performing a leave-one out (LOO) cross-validation study with cross-validation q(2) and conventional r(2) values of 0.779 and 0.989, respectively. The results provide the tools for predicting the affinity of related compounds, and for guiding the design and synthesis of new HPPD ligands with predetermined affinities.

Wen-chao Yang – One of the best experts on this subject based on the ideXlab platform.

  • Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4Hydroxyphenylpyruvate Dioxygenase Inhibitors.
    Journal of agricultural and food chemistry, 2020
    Co-Authors: Qiong Chen, Hong-yan Lin, Ge-fei Hao, Wen-chao Yang, Guang-fu Yang
    Abstract:

    4Hydroxyphenylpyruvate Dioxygenase (HPPD, EC 1.13.11.27) has been identified as one of the most significant targets in herbicide discovery for resistant weed control. In a continuing effort to dis…

  • Pyrazole–Isoindoline-1,3-dione Hybrid: A Promising Scaffold for 4Hydroxyphenylpyruvate Dioxygenase Inhibitors
    Journal of agricultural and food chemistry, 2019
    Co-Authors: Jin Dong, Hong-yan Lin, Ge-fei Hao, Wen-chao Yang, Qiong Chen, Meng-yao Wang, Bai-feng Zheng, Guang-fu Yang
    Abstract:

    The discovery of 4Hydroxyphenylpyruvate Dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 μM to over 1 μM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4– carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 A. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.

  • pyrazole isoindoline 1 3 dione hybrid a promising scaffold for 4 Hydroxyphenylpyruvate Dioxygenase inhibitors
    Journal of Agricultural and Food Chemistry, 2019
    Co-Authors: Jin Dong, Hong-yan Lin, Guang-fu Yang, Ge-fei Hao, Wen-chao Yang, Qiong Chen, Meng-yao Wang, Bai-feng Zheng
    Abstract:

    The discovery of 4Hydroxyphenylpyruvate Dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 μM to over 1 μM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4– carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 A. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.