Neuroprotective role of hydroxychloroquine and trimebutine in alzheimer’s disease: Network pharmacology and molecular simulations
TL;DR
An integrated in silico approach consisting of network pharmacology, molecular docking, molecular dynamics simulation, gene expression profiling using AlzData and cell permeability analysis was used to evaluate the therapeutic efficacy of Trimebutine and Hydroxychloroquine against Alzheimer's disease, establishing stable interactions against AD key targets.
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative pathology worldwide and is marked by the progressive loss of neurons. The current therapeutic armamentarium, which is composed mostly of cholinesterase inhibitors, only provides symptomatic amelioration and is often plagued with undesirable adverse events when chronically administered. Consequently, identification of safer and more efficacious therapeutic alternatives is imperative. Drug repurposing is an inexpensive and time-saving way to uncover new clinical uses for already existing pharmacological agents in the context of AD management. In the current study, an integrated in silico approach consisting of network pharmacology, molecular docking, molecular dynamics (MD) simulation, gene expression profiling using AlzData and cell permeability analysis was used to evaluate the therapeutic efficacy of Trimebutine and Hydroxychloroquine against Alzheimer's disease. The probable target proteins' protein-protein interaction (PPI) network demonstrated non-random connectedness, indicating strong functional linkages. The KEGG pathway enrichment analysis showed that PI3K and Akt are involved in endothelial growth factor (VEGF)-mediated angiogenesis, longevity regulation, and gefitinib resistance pathways, suggesting possible roles in neuroprotection and vascular health. Molecular docking experiments indicated that Trimebutine had a strong sequence homology with 5UBR and 2Y3A, with binding energies of -7.3 and -7.2 kcal/mol, respectively, whereas Hydroxychloroquine bound to 2Y3A at a greater level (-7.0 kcal/mol). Molecular dynamics (MD) simulation validated the stability of the docked complexes, characterized by low RMSD trajectories and persistent hydrogen bond interactions. Both drugs had passive membrane permeability limits, while hydroxychloroquine was somewhat more membrane affine. Trimebutine and Hydroxychloroquine established stable interactions against AD key targets, especially in the PI3K-Akt system, thereby supporting their candidature as repurposed therapeutics for Alzheimer's disease.