Integrative network pharmacology, molecular docking and network-based drug repurposing reveal therapeutic targets and repurposable drugs for obesity-associated type 2 diabetes mellitus
Md. Mainuddin Hossain, Fatematuz Zuhura Evamoni, Md. Mahbub Morshed · In Silico Research in Biomedicine · 2025
Obesity, a progressive metabolic disorder characterized by excessive adiposity, significantly contributes to the development and progression of type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying this association and potential therapeutic interventions remain poorly understood. This study applied an integrative approach combining network pharmacology, molecular docking, and drug repurposing to identify shared molecular targets and candidate drugs. Disease-associated genes were retrieved from GeneCards, CTD, and DisGeNET, followed by protein–protein interaction network construction using STRING and visualization in Cytoscape. Hub genes were determined via CytoHubba and validated through literature mining. Functional enrichment analysis of Gene Ontology terms and KEGG pathways was conducted using DAVID. Additionally, 804 off-patent compounds from the ChemDiv database were screened through molecular docking to assess binding affinities with hub proteins. A 100-nanosecond molecular dynamics simulation was subsequently performed to evaluate the stability and conformational dynamics of selected protein–ligand complexes. Our analysis revealed 23 genes common to obesity and T2DM, with PPARG, IL6, AKT1, TNF, and HMOX1 as key hubs. These were enriched in adipocytokine signaling, insulin resistance, AGE–RAGE signaling, TNF, Toll-like receptor, IL-17, and HIF-1 pathways. Network-based screening identified 14 FDA-approved off-patent drugs, among which simvastatin and estradiol demonstrated strong and stable interactions with all 5 hub proteins compared to control drugs dapagliflozin and empagliflozin. These findings highlight PPARG, IL6, AKT1, TNF, and HMOX1 as key therapeutic targets and propose simvastatin and estradiol as promising repurposable candidates for obesity-associated T2DM management. This integrative framework provides a systematic strategy for identifying multi-target therapeutic options.