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

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 Pithecellobium dulce.

Objective: Only a few experimental in vivo 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.

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. In silico docking studies were also performed to exploring anti-oxidant enzyme-based targets.

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 (S-NG and R-NG)with anti-oxidant enzymes. The binding affinity of S-NG with catalase, GPx, ALP, and SGPT was -10.1, -7.1, -7.1, and -7.3 kcal/mol, respectively, whereas for R-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.

Conclusion: Treatment with NG significantly reduced MTX-induced pancytopenia, renal, and hepatic toxicity.