Systematic Repurposing of Clinically Approved Drugs for Type 2 Diabetes Mellitus through Integrative Computational and Experimental Validation

Abstract

Type 2 diabetes mellitus (T2DM) is a major global health challenge affecting millions of individuals worldwide. Although several pharmacological agents are currently available for diabetes management, they do not offer a permanent cure for this chronic metabolic disorder. Therefore, the present study adopted a drug repurposing strategy to identify FDAapproved drugs with enhanced antidiabetic potential. Glutamine: fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of the hexosamine biosynthetic pathway, was selected as the primary therapeutic target. A library of FDA-approved drugs was subjected to high-throughput virtual screening against GFAT to identify promising candidate drugs. To elucidate the underlying multi-target mechanisms, a network pharmacology and pathway enrichment analysis was subsequently performed. Drug-associated protein targets were predicted and intersected with T2DM-related genes to identify overlapping therapeutic targets, followed by network construction and topological analysis to determine key hub genes. Among the screened drugs, Ixabepilone, Capmatinib, Trilaciclib, Romidepsin, Ibrutinib and Flurandrenolide exhibited extensive interactions with T2DM-associated targets. Pathway enrichment and network topology analyses highlighted ixabepilone as a prominent candidate with high network connectivity and strong association with T2DM-related signaling pathways.