Mechanism of nimodipine in treating neurodegenerative diseases: in silico target identification and molecular dynamic simulation.

Aim: Nimodipine has shown neuroprotective effects in several studies; however, the specific targets and mechanisms remain unclear. This study aims to explore the potential targets and mechanisms of nimodipine in the treatment of neurodegenerative diseases (NDDs), providing a theoretical foundation for repurposing nimodipine for NDDs. Methods: Drug-related targets were predicted using SwissTargetPrediction and integrated with results from CTD, GeneCards, and DrugBank. These targets were then cross-referenced with disease-related targets retrieved from CTD to identify overlapping targets. The intersecting targets were imported into STRING to construct a protein-protein interaction (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R package ClusterProfiler. Molecular docking was carried out using AutoDock Vina, and the ligand-receptor complexes with the highest binding affinities were further simulated using GROMACS to assess the dynamic structural stability and interactions between the ligand and receptor in the dynamic system. Results: A total of 33 intersecting drug-disease targets were identified. After constructing the PPI network and removing isolated targets, the network contained 28 nodes and 69 edges. Network degree analysis combined with enrichment analysis highlighted 12 key targets: CASP3, TNF, BAX, BCL2, IL1B, GSK3B, IL1A, MAOB, MAOA, BDNF, APP, and GFAP. Molecular docking analysis revealed binding energies greater than -6 kcal/mol for MAOA, GSK3B, MAOB, CASP3, BCL2, IL1B and APP. MAOA, with the highest binding energy of -7.343 kcal/mol, demonstrated a stable structure in a 100ns dynamic simulation with nimodipine, exhibiting an average dynamic binding energy of -52.39 ± 3.05 kcal/mol. The dynamic cross-correlation matrix (DCCM) of nimodipine resembled that of harmine, reducing the interactions between protein residues compared to the apo state (regardless of positive or negative correlations). Furthermore, nimodipine induced new negative correlations in residues 100-200 and 300-400. Conclusion: Nimodipine binds to the internal pocket of MAOA and shows potential inhibitory effects. Given its brain-enrichment characteristics and proven neuroprotective effects, it is hypothesized that nimodipine may exert therapeutic effects on NDDs by inhibiting MAOA activity and modulating cerebral oxidative stress. Thus, MAOA emerges as a promising new target for nimodipine in the treatment of NDDs.