miRNAs mediated Hsa21 gene suppression as potential therapeutic agent for Down syndrome: molecular dynamics and...

Down syndrome is a genetic condition caused by trisomy of chromosome 21, leading to intellectual and physical disabilities. Overexpression of the dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21, plays a critical role in neurodevelopmental abnormalities and synaptic dysfunction associated with the disorder. Identifying regulatory mechanisms capable of suppressing DYRK1A expression represents a promising therapeutic strategy.

In this study, a consensus-based computational pipeline was employed to identify microRNAs (miRNAs) targeting DYRK1A. Candidate miRNAs were screened using three publicly accessible databases (miRDB, miRWalk, and TargetScan) with stringent score thresholds. Shortlisted miRNAs were further evaluated through hybridization energy analysis, RNA-RNA interaction validation, secondary structure prediction, exploratory protein-RNA docking with DYRK1A, long-timescale molecular dynamics (600 ns) simulations, and MM/PBSA binding free-energy calculations using the ff19SB force field.

Among the screened candidates, variants of hsa-miR-155-5p consistently emerged as the top miRNAs targeting DYRK1A. Their selection was supported by favorable hybridization energies, stable secondary structures, strong docking interactions with DYRK1A, low RMSD and RMSF values indicating structural stability during 600 ns molecular dynamics simulations, and highly favorable MM/PBSA binding free energies. Together, these metrics indicate robust and sustained interactions with the DYRK1A target.

The integrated computational analyses identify hsa-miR-155-5p as a potential post-transcriptional regulator of DYRK1A, suggesting its relevance as a therapeutic lead for Down syndrome. While these findings provide convergent in silico evidence, experimental validation is required to confirm the biological efficacy and specificity of the proposed miRNA candidates.