Construction and Assessment of Reaction Models of Class I EPSP Synthase: Molecular Docking and Density Functional Theoretical Calculations

Ramalho, Teodorico C.; Caetano, Melissa Soares; Cunha, Elaine F. F. da; Souza, Thais C.S.; Rocha, Marcus V. J.

doi:10.1080/07391102.2009.10507309

Cited by 68 publications

(22 citation statements)

References 35 publications

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“…The partial charges of the atoms were elucidated via the Chelpg method [ 34 ]. The ligands were docked within the crystallographic structure of both AChE species by employing the Molegro Virtual Docker software (MVD®) [ 38 ], considering the same procedures previously employed [ 39 – 41 ]. For the docking procedure, within a radius of 8 Å, water molecules and amino acid residues were considered as flexible.…”

Section: Methodsmentioning

confidence: 99%

A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase

Kuča

Musílek

Jun

et al. 2018

BMC Pharmacol Toxicol

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BackgroundBased on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes.MethodsTo determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6).ResultsReactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min− 1. M− 1, which was 51 times higher than that obtained for obidoxime (kr = 42 min− 1. M− 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE.DiscussionAccording to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.

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Section: Methodsmentioning

confidence: 99%

A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase

Kuča

Musílek

Jun

et al. 2018

BMC Pharmacol Toxicol

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“…From these calculations, the energetic barrier of the reactivation process of each enzyme-OP complex with trimedoxime was determined. This theoretical strategy has been previously employed in other works [26,[39][40][41][42][43][44]. The QM part of the calculations was performed through the Gaussian 09 package, at the DFT level and 6-31g(d,p) basis set [45,46].…”

Section: Qm/mm Proceduresmentioning

confidence: 99%

Understand the interaction modes and reactivity of trimedoxime toward MmAChE inhibited by nerve agents: theoretical and experimental Aspects

Castro

Polisel

Pereira

et al. 2020

Preprint

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The organophosphorus compounds (OP) are used as both chemical weapons and pesticides. However, these agents are very dangerous and toxic to humans, animals, and the environment. Thus, investigations with reactivators have been deeply developed in order to design new antidotes with better efficiency, as well as greater spectrum of action in the AChE reactivation process. With that in mind, in this work, we investigated the behavior of trimedoxime toward the Mus musculus Acetylcholinesterase (MmAChE) inhibited by a range of nerve agents, such as chemical weapons. From experimental essays, reactivation percentages were obtained for the reactivation of different AChE-OP complexes. On the other hand, theoretical calculations were performed to assess the differences of interaction modes and reactivity of trimedoxime within AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most case, showed better reactivation percentages at higher concentrations, with the best result for the reactivation of the AChE-VX adduct. From this work, it was revealed that the mechanistic process contributes most to the oxime efficiency than the interaction in the site. In this way, this study was important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes.

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“…The MolDock scoring function employed in the MVD program comes from the piecewise linear potential (PLP), a simplified potential whose parameters are fitted to protein-ligand structures, binding data scoring functions and further extended in Generic Evolutionary Method for molecular docking with a new hydrogen bonding term and new charge schemes (Ramalho et al, 2009). E PLP stands for ''piecewise linear potential'', which consists of using two different parameter sets described as follows: one for approximation of the steric term (Van der Waals) among atoms, and the other potential for hydrogen binding (Thomsen and Christensen, 2006).…”

Section: Docking Proceduresmentioning

confidence: 99%

Biotransformation of disperse dyes using nitroreductase immobilized on magnetic particles modified with tosyl group: Identification of products by LC-MS-MS and theoretical studies conducted with DNA

Franco

Silva

Castro

et al. 2018

Environmental Pollution

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The present work evaluates the action of nitroreductase enzyme immobilized on Tosylactivated magnetic particles (MP-Tosyl) on three disperse dyes which contain nitro and azo groups. The dyes included Disperse Red 73 (DR 73), Disperse Red 78 (DR 78), and Disperse Red 167 (DR 167). The use of a magnet enabled the rapid and easy removal of the immobilized enzyme after biotransformation; this facilitated the identification of the products generated using high-performance liquid chromatography with diode array detector (HPLC-DAD) and mass spectrometry (LC-MS/MS). The main products formed by the in vitro biotransformation were identified as the product of nitro group reduction to the correspondent amine groups, which were denoted as follows: 50% of 2-(2-(4-((2-cyanoethyl)(ethyl)amino)phenyl)hydrazinyl)-5-nitrobenzonitrile, 98% of 3-((4-((4-amino-2-chlorophenyl) diazenyl)phenyl) (ethyl)amino)propanenitrile and 99% of (3-acetamido-4 - ((4-amino-2-chlorophenyl) diazenyl) phenyl) azanediyl) bis (ethane-2,1-diyl) for DR 73, DR 78 and DR 167, respectively. Based on the docking studies, the dyes investigated were found to be biotransformed by nitroreductase enzyme due to their favorable interaction with the active site of the enzyme. Theoretical results show that DR73 dye exhibits a relatively lower rate of degradation; this is attributed to the cyanide substituent which affects the electron density of the azo group. The docking studies also indicate that all the dyes presented significant reactivity towards DNA. However, Disperse Red 73 was found to exhibit a substantially higher reactivity compared to the other dyes; this implies that the dye possesses a relatively higher mutagenic power. The docking results also show that DR 73, DR 78 and DR 167 may be harmful to both humans and the environment, since the mutagenicity of nitro compounds is associated with the products formed during the reduction of nitro groups. These products can interact with biomolecules, including DNA, causing toxic and mutagenic effects.

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Construction and Assessment of Reaction Models of Class I EPSP Synthase: Molecular Docking and Density Functional Theoretical Calculations

Cited by 68 publications

References 35 publications

A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase

A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase

Understand the interaction modes and reactivity of trimedoxime toward MmAChE inhibited by nerve agents: theoretical and experimental Aspects

Biotransformation of disperse dyes using nitroreductase immobilized on magnetic particles modified with tosyl group: Identification of products by LC-MS-MS and theoretical studies conducted with DNA

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