Molecular Docking Studies of Naringenin and its Protective Efficacy against Methotrexate Induced Oxidative Tissue Injury

Author(s):

Suresh S. Dhanisha, Sudarsanan Drishya, Karyath P. Gangaraj , Muliyar K. Rajesh and Chandrasekharan Guruvayoorappan*   Pages 169 - 180 ( 12 )

Abstract:

Background: Although Methotrexate (MTX) possesses a wide clinical spectrum of activity, its toxic side effects on normal cells and drug resistance often hamper its successful outcome. Naringenin (NG) is one of the promising bioactive flavonoids that are extensively found in grapes, citrus fruits, and fruit arils of <i>Pithecellobium dulce.</i> <p> Objective: Only a few experimental <i>in vivo</i> studies on the efficacy of NG against chemotherapeutic drugs have been carried out. Aiming to fill this gap, the present study was carried out to characterize and identify its possible therapeutic targets and also to explore its protective efficacy against MTX-induced tissue damage. <p> Methods: Oxidative stress was induced in mice with MTX (20 mg/kg B.wt), and animals were orally administered with 10 mg/kg B.wt NG for 10 consecutive days. On day 11, all animals were sacrificed, and hematological and serum biochemical parameters were analyzed. The anti-oxidant efficacy of NG against MTX was evaluated by quantifying tissue superoxide dismutase (SOD), glutatione peroxidase (GPx), reduced glutathione (GSH) and catalase along with oxidative stress markers [malondialdehyde (MDA) and nitric oxide (NO)]. Further, the histopathological analysis was performed to confirm the protective efficacy of FPD. <i>In silico</i> docking studies were also performed to exploring anti-oxidant enzyme-based targets. <p> Results: Our results showed that concurrent administration of NG counteracted oxidative stress induced by MTX, as evidenced by increased expression of anti-oxidant markers, decreased expression of renal and hepatotoxicity serum marker enzymes (p <0.05). A molecular docking study was performed using Auto dock vina to understand the mechanism of ligand binding (<i>S</i>-NG and R-NG)with anti-oxidant enzymes. The binding affinity of <i>S</i>-NG with catalase, GPx, ALP, and SGPT was -10.1, -7.1, -7.1, and -7.3 kcal/mol, respectively, whereas for <i>R</i>-NG was -10.8, -7.1, -7.6, and -7.4 kcal/mol, respectively. Further, histopathological analysis affirmed the protective efficacy of NG against MTX-induced hepatic and renal toxicities. <p> Conclusion: Treatment with NG significantly reduced MTX-induced pancytopenia, renal, and hepatic toxicity.

Keywords:

Methotrexate, naringenin, <i>in vivo</i> anti-oxidant activity, toxicity markers, target prediction analysis, molecular docking.

Affiliation:

Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, Division of Crop improvement, ICAR-Central Plantation Crops Research Institute, Kasaragod 671124, Kerala, Division of Crop improvement, ICAR-Central Plantation Crops Research Institute, Kasaragod 671124, Kerala, Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Trivandrum-695 011, Kerala

Graphical Abstract:

Read Full-Text article