Molecular insight into the inhibition mechanism of plant and rat 4-hydroxyphenylpyruvate dioxygenase by molecular docking and DFT calculations

Silva, Telles Cardoso; Pires, Marcus Sandes; Castro, Alexandre A. de; Cunha, Elaine F. F. da; Caetano, Melissa Soares; Ramalho, Teodorico C.

doi:10.1007/s00044-015-1436-3

Cited by 25 publications

(17 citation statements)

References 44 publications

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“…Because of emergence of sulcotrione resistant, therefore obtaining HPPD inhibitors with novel scaffolds is an urgent task for herbicide developers. The inhibitory mechanism has been found in previous studies (Lin et al, 2013 ; Silva et al, 2015 ). In HPPD, active site Fe(II) octahedral coordination sphere is accomplished by forming coordinating interaction with three protein ligand atoms and three water molecules.…”

Section: Introductionsupporting

confidence: 75%

Combination of Virtual Screening Protocol by in Silico toward the Discovery of Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Sun

et al. 2018

Front. Chem.

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4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a potent new bleaching herbicide target. Therefore, in silico structure-based virtual screening was performed in order to speed up the identification of promising HPPD inhibitors. In this study, an integrated virtual screening protocol by combining 3D-pharmacophore model, molecular docking and molecular dynamics (MD) simulation was established to find novel HPPD inhibitors from four commercial databases. 3D-pharmacophore Hypo1 model was applied to efficiently narrow potential hits. The hit compounds were subsequently submitted to molecular docking studies, showing four compounds as potent inhibitor with the mechanism of the Fe(II) coordination and interaction with Phe360, Phe403, and Phe398. MD result demonstrated that nonpolar term of compound 3881 made great contributions to binding affinities. It showed an IC50 being 2.49 μM against AtHPPD in vitro. The results provided useful information for developing novel HPPD inhibitors, leading to further understanding of the interaction mechanism of HPPD inhibitors.

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Section: Introductionsupporting

confidence: 75%

Combination of Virtual Screening Protocol by in Silico toward the Discovery of Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Sun

et al. 2018

Front. Chem.

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“…For this work, considering that the chiral carbon is irrelevant to determine the toxicity of this neurotoxic agent, an equal pair of stereoisomers considering both chiral centers ( R , R P ) and ( S , S P ) was thus chosen [ 7 ]. The R P and S P stereoisomers of these compounds were individually docked inside the crystallographic structure of DFPase (PDB code 2GVV; resolution = 1.73 Å) [ 13 ], using the Molegro Virtual Docker program (MVD ® ) [ 21 ], taking into account the same procedures employed in other studies and the previous removal of the original ligand DcPPA [ 22 , 23 , 24 ]. For the development of the docking calculations, it was considered a radius of 5 Å centered at the active site, with the residues being kept as flexible.…”

Section: Methodsmentioning

confidence: 99%

Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication

Soares

Castro

Pereira

et al. 2018

IJMS

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Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways.

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“…The compounds were then docked inside the crystallographic structure of viral protein M pro (PDB code 6LU7; resolution = 2.16 Å), [25] using the Molegro Virtual Docker program (MVD®), [26] taking into account the same procedures employed previously. [27][28][29] According to our calculation protocol, it was considered a radius of about 20 Å, where the residues of the catalytic triad were kept as exible. Due to the nature of the docking methods, the calculations were carried out, generating approximately 50 poses (hence such as conformation and orientation) for each ligand studied.…”

Section: Computational Detailsmentioning

confidence: 99%

New in silico insights into the application of the (hydroxy)chloroquine with macrolide antibiotics co-crystals against the SARS-CoV-2 virus

Castro¹,

Assis²,

Ramalho³

et al. 2020

Preprint

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In this in silico study, the different pharmaceutical co-crystals based on the (hydroxy)chloroquine with the macrolide antibiotics (azithromycin, clarithromycin, or erythromycin A) was analyzed for the first time. These findings present a new molecular perspective and, therefore, suggest that the combination of (hydroxy)chloroquine/azithromycin, in the stoichiometric ratio of 1:1, as model co-crystals systems have less toxicity as well as is the most effective for inhibiting the new coronavirus SARS-CoV-2.

show abstract

Molecular insight into the inhibition mechanism of plant and rat 4-hydroxyphenylpyruvate dioxygenase by molecular docking and DFT calculations

Cited by 25 publications

References 44 publications

Combination of Virtual Screening Protocol by in Silico toward the Discovery of Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Combination of Virtual Screening Protocol by in Silico toward the Discovery of Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication

New in silico insights into the application of the (hydroxy)chloroquine with macrolide antibiotics co-crystals against the SARS-CoV-2 virus

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