In silico design and molecular docking evaluation of antisense oligonucleotides targeting IDO1 mRNA in the context of depression

Depression is a prevalent mental disorder worldwide, often accompanied by severe complications that significantly impair patients’ daily lives. Indoleamine-2,3-dioxygenase 1 (IDO1), a key metabolic enzyme in the kynurenine pathway, is considered a promising therapeutic target for depression treatment. Antisense oligonucleotides (ASOs) are small nucleic acid drugs characterized by high specificity, high potency, minimal drug-drug interactions, a prolonged duration of action, and a low risk of off-target activity, making them effective tools for targeting molecules previously considered undruggable. Consequently, this study designed a novel ASO targeting the IDO1 gene using a computational approach as a fundamental basis for further investigation. Based on rational design criteria, five candidate ASOs were screened and utilized for molecular docking simulations with their corresponding IDO1 mRNA fragments. Furthermore, the intermolecular interactions and binding affinities of the resulting complexes were comprehensively evaluated. The results demonstrated that strong interactions were established across the five complexes. Among them, ASO1 displayed the strongest binding affinity. Notably, its binding site is located within the coding region (CDS) of the mRNA, suggesting its potential to effectively inhibit IDO1 gene expression and exert therapeutic efficacy for depression.