Unique and overlapping mechanisms of valbenazine, deutetrabenazine, and vitamin E for tardive dyskinesia

In 2017, the Food and Drug Administration (FDA) approved valbenazine and deutetrabenazine, two vesicular monoamine transporter 2 (VMAT2) inhibitors, as treatments for tardive dyskinesia (TD). Additionally, some trials have suggested that vitamin E may benefit TD patients. However, the mechanistic basis for these treatments remains unclear. The objective of this study was to analyze and compare the mechanisms of valbenazine, deutetrabenazine, and vitamin E in TD treatment utilizing network pharmacology and molecular docking approaches. Putative target genes associated with valbenazine, deutetrabenazine, and vitamin E were retrieved from the PharmMapper, CTD, GeneCards, SwissTargetPrediction, and DrugBank databases. TD-related targets were identified using the GeneCards, DisGeNET, OMIM, and TTD databases. A protein-protein interaction (PPI) network was created to identify core targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via DAVID, and Cytoscape was used to build a drug-pathway-target-disease network. Molecular docking evaluated drug-target interactions. A total of 32, 36, and 62 targets relevant to the treatment of TD were identified for valbenazine, deutetrabenazine, and vitamin E, respectively. PPI and KEGG pathway analyses suggested that valbenazine and deutetrabenazine may influence TD through the dopaminergic synapse signaling pathway via common core targets (e.g., Dopamine Receptor D1 (DRD1), DRD2, Monoamine Oxidase B (MAOB), Solute Carrier Family 6 Member 3 (SLC6A3), SLC18A2) and specific targets (DRD3 for valbenazine, MAOA for deutetrabenazine). Vitamin E may affect TD by targeting the PI3K-Akt pathway through AKT Serine/Threonine Kinase 1 (AKT1), Brain-Derived Neurotrophic Factor (BDNF), Insulin (INS), Nitric Oxide Synthase 3 (NOS3), and Toll-Like Receptor 4 (TLR4). This study provides insights into the common and unique molecular mechanisms by which valbenazine, deutetrabenazine, and vitamin E may treat TD. Pharmacological experiments should be conducted to verify and further explore these results. The findings offer a theoretical basis for further pharmacological investigation and a resource for TD drug screening.