In-silico repurposing of imeglimin against Alzheimer’s disease using network pharmacology, molecular docking and molecular dynamic simulations approaches

Imeglimin is a novel Glimins-class medication approved in Japan for Type 2 diabetes (T2DM) treatment. The mechanism of action of imeglimin’s includes improvement in insulin action and prevents β cell dysfunction. Insulin receptors are also found in the brain and their dysfunction are associated to Alzheimer's disease (AD). The main focus of the present studies was to examine the repurposing potential of imeglimin, an anti-diabetic medication against AD, utilizing network pharmacology, molecular docking and molecular dynamic simulations (MDS). The AD targets and imeglimin targets were retrieved from several databases and 90 common target proteins were retrieved from VENN.2.0 which were associated with AD and T2DM. From the common genes PPI network was generated to identify the top 10 hub proteins. KEGG and GO term analysis revealed that repurposing potential of imeglimin and AD involves PI3Akt signalling pathway, neuroactive ligand interaction, G-Protein coupled receptor serotonin signalling pathway and Alzheimer’s disease. The molecular docking studies was performed to check the binding modes of imeglimin against these top 10 hub proteins with their bound X-ray ligand in AutoDock Vina program. The imeglimin was observed with satisfactory binding potential against only top 4 AD targets: CHRNA4 (-4.8 kcal/mol), SLC6A2 (6.1 kcal/mol), SLC6A3 (-5.3 kcal/mol) and HSP90AA1 (-3.7 kcal/mol). However, MDS studies (in Desmond program till 200 ns) were shortlisted only top 3 novel AD targets (CHRNA4, SLC6A2 and SLC6A3) on the basis stability parameters (RMSD, RMSF, Rg and dG) which exhibited the high stability of Imeglimin in their active site as compared to X-ray ligand. The donepezil (clinically approved acetylcholinesterase inhibitor for AD) was also exhibited the binding potential against these three novel AD targets during docking studies. These in-silico repurposing studies revealed that the imeglimin had the binding potential against these novel anti-AD targets, but this must be validated experimentally.