Structural Dynamics and Network Pharmacology for the Discovery of Inhibitors Targeting DYRK1 A in Neurological Disorders.

Neurological disorders, including Down syndrome, Alzheimer's disease, and autism spectrum disorders, involve intricate disruptions in brain function and development. DYRK1A (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) has become an essential target in these diseases because it helps neurons grow, differentiate, and change shape. Overexpression of DYRK1A is connected to problems with neurodevelopment, memory loss, and tauopathies, which makes it an essential target for therapy. Therefore, inhibiting the DYRK1A protein aids in maintaining the normal brain molecular mechanism. Herein, we have identified three major natural compounds, ZINC000043552589, ZINC000001562130, and ZINC000059779788, as potential inhibitory candidates. These compounds exhibited a strong binding affinity with the DYRK1A protein during virtual screening and molecular docking. During the virtual screening analysis, the binding scores of these compounds were more than -11.0 kcal/mol. Further, hydrogen and hydrophobic interactions strengthen their binding with the DYRK1A protein. The MD simulation analysis also confirmed the structural dynamic stability of the compounds. Moreover, the total free binding energy calculated via the MM/GBSA method was found to be -54.06 kcal/mol for ZINC000043552589, -39.01 kcal/mol for ZINC000001562130 and -50.26 kcal/mol for ZINC000059779788. These values further confirm the binding affinity strength of the compounds with the target protein. DFT analysis revealed distinct HOMO-LUMO energy gaps and orbital distributions across the compounds, highlighting their varied electronic characteristics and charge-transfer potentials. Network pharmacology analysis further highlighted multiple potential gene targets for the selected compounds, providing insights into their broader therapeutic implications. This analysis suggests these natural compounds may modulate additional pathways relevant to neurodevelopmental and neurodegenerative diseases.