Integrated Network
Pharmacology and Molecular Docking to understand the Mechanisms of Methotrexate-induced
Intestinal Toxicity
Charles Doveit Antony, Katturajan Ramkumar, Thirunavukarasu Muthu Kumar and Evan
Prince Sabina
Res. J. Biotech.; Vol. 20(11); 120-127;
doi: https://doi.org/10.25303/2011rjbt1200127; (2025)
Abstract
Methotrexate, a versatile therapeutic agent, is associated with significant intestinal
toxicity, posing clinical challenges. To comprehensively elucidate the underlying
mechanisms, we employed an integrated approach combining network pharmacology and
molecular docking. Our study identified 155 common targets associated with methotrexate
and intestinal toxicity. Network analysis unveiled pivotal nodes, highlighting the
TNF signaling pathway and PI3K-AKT signaling pathway. Gene ontology and KEGG pathway
enrichment analysis revealed associations with inflammation, apoptosis and immune
responses. The constructed D-C-T-P-D network illuminated complex interactions between
methotrexate, target genes, pathways and diseases, emphasizing key targets including
TNF, AKT1, CASP3 and others. Molecular docking simulations demonstrated robust binding
affinities between methotrexate and these targets. AKT1 and CASP3 exhibited the
strongest interactions, suggesting their pivotal roles in methotrexate-induced intestinal
damage.
Our findings provide insights into the molecular basis of this adverse effect, offering
potential therapeutic targets for intervention. However, further experimental validation
and consideration of individual patient factors are warranted to translate these
discoveries into clinical practice. This underscores the need for personalized approaches
to mitigate methotrexate-induced intestinal toxicity.
