Discovery of a new non-substrate inhibitor of the 26.5 kDa glutathione transferase from Taenia solium by virtual screening

García-Gutiérrez, Ponciano; Zubillaga, Rafael A.; Téllez-Plancarte, Alexandro; Flores-López, Roberto; Camarillo-Cadena, Menandro; Landa, Abraham

doi:10.1016/j.jmgm.2020.107707

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…The scoring function is a key component in docking worthy of further development and demonstrates that it has the power to design new small molecules. However, flexible interactions between coumarin molecules and GST receptors (Güller, 2021), in addition to experimental technology, in silico docking can bring the study to a good level (García‐Gutiérrez et al., 2020).…”

Section: Resultsmentioning

confidence: 99%

The effects of Daucus carota extract against PC3, PNT1a prostate cells, acetylcholinesterase, glutathione S‐transferase, and α‐glycosidase; an in vitro–in silico study

et al. 2021

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Daucus carota L. ssp. major (DCM) plant is widely used in traditional medicine to treat some types of cancer and various diseases. Therefore, we evaluated the biological activities of this plant to define its effects against prostate cancer (PCa), Alzheimer’s disease (AD), oxidation, and diabetes mellitus (DM) as well as identified its phenolic composition. To determine the anti‐cancer properties of the plant extract, we treated PCa cells with the extract at a concentration range of 0.25, 0.5, 1, 2, and 4 mg/ml. Significant results were obtained against the PC3 cells compared to normal PNT1a prostate epithelial cells. As a result of precise measurements at the millimolar level, it was observed that the plant extract showed an effective inhibition (IC50) against glutathione S‐transferase (GST; 12.84 mM), acetyl cholinesterase (AChE; 15.07 mM), and α‐Gly (11.75 mM) enzymes when compared with standard inhibitors. Antioxidant activities of DCM methanol extract were determined via two well‐known in vitro techniques. The extracts showed antioxidant activities against the DPPH and ABTS+. The LC‐ESI‐MS/MS was used to determine the phenolic compounds of methanol extract from DCM. Chlorogenic acid (2,089.096 µg/g), shikimic acid (193.14 µg/g), and coumarin (113.604 µg/g) were characterized as major phenolic compounds. In addition, the interactions of chlorogenic acid, chrysin, coumarin, and shikimic acid with the used three enzymes have been calculated using molecular docking simulation. Practical applications Plant natural phenolic compounds have protective effects such as anti‐inflammatory, antioxidant, anticarcinogen, and enzyme inhibitory. Therefore, it has an important place in the food and pharmaceutical industry. The present study aims to reveal the enzyme inhibitory, antioxidant, and anticarcinogenic properties of the Daucus carota ssp. Major (DCM) plant extract. Significant results were obtained against the PC3 cells compared to normal PNT1a prostate epithelial cells. DCM extract demonstrated considerable antioxidant activity and inhibitory potential on used metabolic enzymes. These biological effects are thought to have a relationship with rich chemical composition.

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Section: Resultsmentioning

confidence: 99%

The effects of Daucus carota extract against PC3, PNT1a prostate cells, acetylcholinesterase, glutathione S‐transferase, and α‐glycosidase; an in vitro–in silico study

et al. 2021

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“…Kinetic analyses performed at different concentrations of GSH and CDNB produced intersecting double-reciprocal plots that provided evidence of ternary complex formation during enzymatic conjugation [70]. Furthermore, because the intersection occurred on the abscissa, the mechanism proceeds through the random sequential binding of co-substrates [71].…”

Section: Kinetic Mechanism Of Ts26gst In the Cdnb Conjugation Reactionmentioning

confidence: 98%

“…A homology model for Ts26GST was built from the structure of Fasciola hepatica M-class GST (PDB ID 2FHE), whose sequence has 47% identity, with 96% query coverage [70]. The analysis of this model with PROCHECK showed that 91.5% of residues are in favored regions in the Ramachandran plot, with no residues in the disallowed region.…”

Section: Structural Similarity Of Ts26gst To Human Cgstsmentioning

confidence: 99%

Development of New Drugs to TreatTaenia soliumCysticercosis: Targeting 26 kDa Glutathione Transferase

Zubillaga¹,

Jiménez²,

García-Gutiérrez³

et al. 2021

Current State of the Art in Cysticercosis and Neurocysticercosis

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Taenia solium causes neurocysticercosis, a parasitic infection of the central nervous system in humans. The costs of management, treatment, and diagnosis of patients with neurocysticercosis are high, and some patients do not respond to the currently available treatments. Helminth cytosolic glutathione transferases (GSTs) are essential enzymes involved in the regulation of immune responses, transport, and detoxification. In T. solium, three cytosolic GSTs with molecular masses of 26.5 (Ts26GST), 25.5 (Ts25GST), and 24.3 kDa (TsMσGST), classified as mu-alpha, mu and sigma GST-classes, respectively, constitute the main detoxification system, and they may be immune targets for the development of vaccines and new anthelmintics. We performed a successful virtual screen, and identified I7, a novel selective inhibitor of Ts26GST that showed a non-competitive inhibition mechanism towards substrate glutathione with a Ki of 55.7 mM and mixed inhibition towards the electrophilic substrate 1-chloro-2,4-dinitrobenzene with a Ki of 8.64 mM. Docking simulation studies showed that I7 can bind to a site that is adjacent to the electrophilic site and the furthest from the glutathione site. This new inhibitor of Ts26GST will be used as a lead molecule to develop new effective and safe drugs against diseases caused by T. solium.

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“…Because mammalian hosts also possess GSTs, it is important that, in the search for inhibitors of helminth GSTs, the structures of the host’s homologous GSTs are also considered in the selection of drug binding sites in which there are few common residues, as this would achieve better selectivity toward the parasite enzyme [ 86 ].…”

Section: Structural and Functional Generalities Of Gstσmentioning

confidence: 99%

Sigma-Class Glutathione Transferases (GSTσ): A New Target with Potential for Helminth Control

Sánchez Pérez,

Zubillaga,

García-Gutiérrez

et al. 2024

TropicalMed

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Glutathione transferases (GSTs EC 2.5.1.18) are critical components of phase II metabolism, instrumental in xenobiotics’ metabolism. Their primary function involves conjugating glutathione to both endogenous and exogenous toxic compounds, which increases their solubility and enables their ejection from cells. They also play a role in the transport of non-substrate compounds and immunomodulation, aiding in parasite establishment within its host. The cytosolic GST subfamily is the most abundant and diverse in helminths, and sigma-class GST (GSTσ) belongs to it. This review focuses on three key functions of GSTσ: serving as a detoxifying agent that provides drug resistance, functioning as an immune system modulator through its involvement in prostaglandins synthesis, and acting as a vaccine antigen.

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Discovery of a new non-substrate inhibitor of the 26.5 kDa glutathione transferase from Taenia solium by virtual screening

Cited by 7 publications

References 46 publications

The effects of Daucus carota extract against PC3, PNT1a prostate cells, acetylcholinesterase, glutathione S‐transferase, and α‐glycosidase; an in vitro–in silico study

The effects of Daucus carota extract against PC3, PNT1a prostate cells, acetylcholinesterase, glutathione S‐transferase, and α‐glycosidase; an in vitro–in silico study

Development of New Drugs to TreatTaenia soliumCysticercosis: Targeting 26 kDa Glutathione Transferase

Sigma-Class Glutathione Transferases (GSTσ): A New Target with Potential for Helminth Control

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