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 4-Hydroxyphenylpyruvate 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:

    4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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, Ge-fei Hao, Wen-chao Yang, Guang-fu Yang, Qiong Chen, Meng-yao Wang, Bai-feng Zheng
    Abstract:

    The discovery of 4-Hydroxyphenylpyruvate 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.

  • Molecular insights into the mechanism of 4-Hydroxyphenylpyruvate Dioxygenase inhibition: enzyme kinetics, X-ray crystallography and computational simulations.
    The FEBS journal, 2019
    Co-Authors: Hong-yan Lin, Ge-fei Hao, Wen-chao Yang, Da-wei Wang, Jing-fang Yang, Jiang‐qing Dong, Yu‐xia Wang, Chang-guo Zhan, Guang-fu Yang
    Abstract:

    Slow-binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off-target rates is restricted by a limited understanding of the structural basis of slow-binding inhibition kinetics in enzyme-drug interactions. 4-Hydroxyphenylpyruvate Dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time-dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow-binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C-terminal α-helix in the inhibitor-bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time-dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD-targeted drugs or herbicides with longer target residence time and improved properties. DATABASE: Structure data are available in the PDB under the accession numbers 5CTO (released), 5DHW (released), and 5YWG (released).

  • Hydrophobicity-oriented drug design (HODD) of new human 4-Hydroxyphenylpyruvate Dioxygenase inhibitors.
    European Journal of Medicinal Chemistry, 2019
    Co-Authors: Ferdinand Ndikuryayo, Wen-chao Yang, Wei-ming Kang, Guang-fu Yang
    Abstract:

    Abstract Involved in the tyrosine degradation pathway, 4-Hydroxyphenylpyruvate Dioxygenase (HPPD) is an important target for treating type I tyrosinemia. To discover novel HPPD inhibitors, we proposed a hydrophobicity-oriented drug design (HODD) strategy based on the interactions between HPPD and the commercial drug NTBC. Most of the new compounds showed improved activity, compound d23 being the most active candidate (IC50 = 0.047 μM) with about 2-fold more potent than NTBC (IC50 = 0.085 μM). Therefore, compound d23 is a potential drug candidate to treat type I tyrosinemia.

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 4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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.

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

    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.

  • 3D-QSAR studies on 4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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.

  • Design, synthesis, and evaluation of postulated transient intermediate and substrate analogues as inhibitors of 4-Hydroxyphenylpyruvate Dioxygenase
    Bioorganic & medicinal chemistry letters, 2002
    Co-Authors: Yun-loung Lin, Jian-lin Huang, Hung-ge Liu, Ding-yah Yang
    Abstract:

    Abstract An epoxybenzoquinone, 4-hydroxyphenoxypropionic acid, and 2-hydroxy-3-phenyl-3-butenoic acid derivatives have been designed, synthesized, and evaluated for in vitro inhibition activity against 4-Hydroxyphenylpyruvate Dioxygenase (4-HPPD) from pig liver by the spectrophotometric enol-borate method. The biological data demonstrated that neither epoxybenzoquinone ester nor 2-hydroxy-3-phenyl-3-butenoic acid is an inhibitor of 4-HPPD. The most potent 4-HPPD inhibitor tested was 3-hydroxy-4-phenyl-2(5H)-furanone with an IC50 value of 0.5 μM, which may serve as a lead compound for further design of more potent 4-HPPD inhibitors.

  • Mode of action of 4-Hydroxyphenylpyruvate Dioxygenase inhibition by triketone-type inhibitors.
    Journal of medicinal chemistry, 2002
    Co-Authors: Jian-lin Huang, Yang-sheng Sun, Ding-yah Yang
    Abstract:

    A series of 2-(2-nitrobenzoyl)cyclohexane-1,3-dione analogues (1-9) were designed, synthesized, and evaluated for inhibition of 4-Hydroxyphenylpyruvate Dioxygenase (4-HPPD), a key enzyme involved in the catabolism of tyrosine which catalyzes the conversion of 4-Hydroxyphenylpyruvate to homogentisate. The correlations between the results of enzyme inhibition, ferric chloride tests, and the conformational analysis suggested that the tight binding between triketone-type inhibitors and 4-HPPD is likely due to chelation of the enzyme-bound ferric iron with the enol tautomer of 1,3-diketone moiety of the triketones. The presence of a 2-carbonyl group in the triketone is an essential structural feature for potent 4-HPPD inhibition. Modification of the 3-carbonyl group of triketone moiety to other functionality will reduce the overall planarity and thus prevent keto-enol tautomerization, resulting in a decrease or lack of inhibition activity.

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 4-Hydroxyphenylpyruvate 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:

    4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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, Ge-fei Hao, Wen-chao Yang, Guang-fu Yang, Qiong Chen, Meng-yao Wang, Bai-feng Zheng
    Abstract:

    The discovery of 4-Hydroxyphenylpyruvate 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.

  • Molecular insights into the mechanism of 4-Hydroxyphenylpyruvate Dioxygenase inhibition: enzyme kinetics, X-ray crystallography and computational simulations.
    The FEBS journal, 2019
    Co-Authors: Hong-yan Lin, Ge-fei Hao, Wen-chao Yang, Da-wei Wang, Jing-fang Yang, Jiang‐qing Dong, Yu‐xia Wang, Chang-guo Zhan, Guang-fu Yang
    Abstract:

    Slow-binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off-target rates is restricted by a limited understanding of the structural basis of slow-binding inhibition kinetics in enzyme-drug interactions. 4-Hydroxyphenylpyruvate Dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time-dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow-binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C-terminal α-helix in the inhibitor-bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time-dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD-targeted drugs or herbicides with longer target residence time and improved properties. DATABASE: Structure data are available in the PDB under the accession numbers 5CTO (released), 5DHW (released), and 5YWG (released).

  • Hydrophobicity-oriented drug design (HODD) of new human 4-Hydroxyphenylpyruvate Dioxygenase inhibitors.
    European Journal of Medicinal Chemistry, 2019
    Co-Authors: Ferdinand Ndikuryayo, Wen-chao Yang, Wei-ming Kang, Guang-fu Yang
    Abstract:

    Abstract Involved in the tyrosine degradation pathway, 4-Hydroxyphenylpyruvate Dioxygenase (HPPD) is an important target for treating type I tyrosinemia. To discover novel HPPD inhibitors, we proposed a hydrophobicity-oriented drug design (HODD) strategy based on the interactions between HPPD and the commercial drug NTBC. Most of the new compounds showed improved activity, compound d23 being the most active candidate (IC50 = 0.047 μM) with about 2-fold more potent than NTBC (IC50 = 0.085 μM). Therefore, compound d23 is a potential drug candidate to treat type I tyrosinemia.

Hong-yan Lin - One of the best experts on this subject based on the ideXlab platform.

  • Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate 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:

    4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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, Ge-fei Hao, Wen-chao Yang, Guang-fu Yang, Qiong Chen, Meng-yao Wang, Bai-feng Zheng
    Abstract:

    The discovery of 4-Hydroxyphenylpyruvate 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.

  • Molecular insights into the mechanism of 4-Hydroxyphenylpyruvate Dioxygenase inhibition: enzyme kinetics, X-ray crystallography and computational simulations.
    The FEBS journal, 2019
    Co-Authors: Hong-yan Lin, Ge-fei Hao, Wen-chao Yang, Da-wei Wang, Jing-fang Yang, Jiang‐qing Dong, Yu‐xia Wang, Chang-guo Zhan, Guang-fu Yang
    Abstract:

    Slow-binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off-target rates is restricted by a limited understanding of the structural basis of slow-binding inhibition kinetics in enzyme-drug interactions. 4-Hydroxyphenylpyruvate Dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time-dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow-binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C-terminal α-helix in the inhibitor-bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time-dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD-targeted drugs or herbicides with longer target residence time and improved properties. DATABASE: Structure data are available in the PDB under the accession numbers 5CTO (released), 5DHW (released), and 5YWG (released).

  • An efficient one-pot synthesis of 2-(aryloxyacetyl)cyclohexane-1,3-diones as herbicidal 4-Hydroxyphenylpyruvate Dioxygenase inhibitors.
    Journal of agricultural and food chemistry, 2016
    Co-Authors: Da-wei Wang, Hong-yan Lin, Wen-chao Yang, Qiong Chen, Tao Chen, Guang-fu Yang
    Abstract:

    4-Hydroxyphenylpyruvate Dioxygenase (EC 1.13.11.27, HPPD) is an important target for new bleaching herbicides discovery. As a continuous work to discover novel crop selective HPPD inhibitor, a series of 2-(aryloxyacetyl)cyclohexane-1,3-diones were rationally designed and synthesized by an efficient one-pot procedure using N,N′-carbonyldiimidazole (CDI), triethylamine, and acetone cyanohydrin in CH2Cl2. A total of 58 triketone compounds were synthesized in good to excellent yields. Some of the triketones displayed potent in vitro Arabidopsis thaliana HPPD (AtHPPD) inhibitory activity. 2-(2-((1-Bromonaphthalen-2-yl)oxy)acetyl)-3-hydroxycyclohex-2-en-1-one, II-13, displayed high, broad-spectrum, and postemergent herbicidal activity at the dosage of 37.5–150 g ai/ha, nearly as potent as mesotrione against some weeds. Furthermore, II-13 showed good crop safety against maize and canola at the rate of 150 g ai/ha, indicating that II-13 might have potential as a herbicide for weed control in maize and canola fiel...

Ge-fei Hao - One of the best experts on this subject based on the ideXlab platform.

  • Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate 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:

    4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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 4-Hydroxyphenylpyruvate 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, Ge-fei Hao, Wen-chao Yang, Guang-fu Yang, Qiong Chen, Meng-yao Wang, Bai-feng Zheng
    Abstract:

    The discovery of 4-Hydroxyphenylpyruvate 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.

  • Molecular insights into the mechanism of 4-Hydroxyphenylpyruvate Dioxygenase inhibition: enzyme kinetics, X-ray crystallography and computational simulations.
    The FEBS journal, 2019
    Co-Authors: Hong-yan Lin, Ge-fei Hao, Wen-chao Yang, Da-wei Wang, Jing-fang Yang, Jiang‐qing Dong, Yu‐xia Wang, Chang-guo Zhan, Guang-fu Yang
    Abstract:

    Slow-binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off-target rates is restricted by a limited understanding of the structural basis of slow-binding inhibition kinetics in enzyme-drug interactions. 4-Hydroxyphenylpyruvate Dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time-dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow-binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C-terminal α-helix in the inhibitor-bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time-dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD-targeted drugs or herbicides with longer target residence time and improved properties. DATABASE: Structure data are available in the PDB under the accession numbers 5CTO (released), 5DHW (released), and 5YWG (released).

  • Synthesis and Herbicidal Activity of Triketone-Quinoline Hybrids as Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.
    Journal of agricultural and food chemistry, 2015
    Co-Authors: Da-wei Wang, Hong-yan Lin, Ge-fei Hao, Wen-chao Yang, Run-jie Cao, Qiong Chen, Tao Chen, Guang-fu Yang
    Abstract:

    4-Hydroxyphenylpyruvate Dioxygenase (EC 1.13.11.27, HPPD) is one of the most important targets for herbicide discovery. In the search for new HPPD inhibitors with novel scaffolds, triketone–quinoline hybrids were designed and subsequently optimized on the basis of the structure–activity relationship (SAR) studies. Most of the synthesized compounds displayed potent inhibition of Arabidopsis thaliana HPPD (AtHPPD), and some of them exhibited broad-spectrum and promising herbicidal activity at the rate of 150 g ai/ha by postemergence application. Most promisingly, compound III-l, 3-hydroxy-2-(2-methoxy-7-(methylthio)quinoline-3-carbonyl)cyclohex-2-enone (Ki = 0.009 μM, AtHPPD), had broader spectrum of weed control than mesotrione. Furthermore, compound III-l was much safer to maize at the rate of 150 g ai/ha than mesotrione, demonstrating its great potential as herbicide for weed control in maize fields. Therefore, triketone–quinoline hybrids may serve as new lead structures for novel herbicide discovery.