Deciphering the Multi-Target Mechanisms of Imeglimin in Type 2 Diabetes Mellitus Through Integrated Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation

Abstract

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder involving insulin resistance, impaired glucose metabolism, mitochondrial dysfunction, and chronic inflammation. Imeglimin is a novel oral antidiabetic agent that improves mitochondrial function and insulin sensitivity, although its precise molecular mechanisms remain incompletely understood. This study employed an integrated network pharmacology approach combined with molecular docking, molecular dynamics (MD) simulation, and external validation to investigate the potential molecular targets and pathways of imeglimin in T2DM. Pharmacokinetic and drug-likeness properties were assessed using SwissADME, Molsoft, and pkCSM. Potential targets predicted by SwissTargetPrediction were intersected with T2DM-associated genes from GeneCards, followed by protein-protein interaction, Gene Ontology, and KEGG enrichment analyses. Molecular docking, redocking validation, 100 ns MD simulations, and MM-GBSA calculations were performed. External validation used DisGeNET and GEO datasets. Imeglimin exhibited favourable pharmacokinetic properties and Lipinski compliance. Forty overlapping targets were identified, with SLC6A3, HTR1A, GRIN2B, HTR2A, HTR2C, CA1, HTR1B, and EGFR as major hubs. Enrichment highlighted PI3K-Akt, dopaminergic synapse, calcium, and cAMP signalling. MD and MM-GBSA analyses supported stable interactions, particularly with SLC6A3, HTR2C, and GSK3B. These findings provide a systems-level basis for further experimental validation of imeglimin mechanisms in T2DM.