The effects of morin and methotrexate on pentose phosphate pathway enzymes and GR/GST/TrxR enzyme activities: An in vivo and in silico study

Abstract

In this study, the mechanisms by which the enzymes glucose‐6‐phosphate dehydrogenase (G6PD), 6‐phosphogluconate dehydrogenase (6PGD), glutathione reductase (GR), glutathione‐S‐transferase (GST), and thioredoxin reductase (TrxR) are inhibited by methotrexate (MTX) were investigated, as well as whether the antioxidant morin can mitigate or prevent these adverse effects in vivo and in silico. For 10 days, rats received oral doses of morin (50 and 100 mg/kg body weight). On the fifth day, a single intraperitoneal injection of MTX (20 mg/kg body weight) was administered to generate toxicity. Decreased activities of G6PD, 6PGD, GR, GST, and TrxR were associated with MTX‐related toxicity while morin treatment increased the activity of the enzymes. The docking analysis indicated that H‐bonds, pi–pi stacking, and pi–cation interactions were the dominant interactions in these enzyme‐binding pockets. Furthermore, the docked poses of morin and MTX against GST were subjected to molecular dynamic simulations for 200 ns, to assess the stability of both complexes and also to predict key amino acid residues in the binding pockets throughout the simulation. The results of this study suggest that morin may be a viable means of alleviating the enzyme activities of important regulatory enzymes against MTX‐induced toxicity.

Protective effects of esculetin against doxorubicin‐induced toxicity correlated with oxidative stress in rat liver: In vivo and in silico studies

“…[32,33] Subsequently, a restrained minimization using the OPLS4 force field [34] was implemented to address overlapping hydrogens. [35] The residues of the active site that were ascertained using the SiteMap tool [36,37] were determined in the module for generating the receptor grid. [38,39] Before molecular docking, DOX and esculetin were also subjected to preparation to generate all possible 3D conformations and states under physiological pH conditions, [40] utilizing the LigPrep module.…”