Structure-guided discovery of tau-phosphorylating kinase DYRK1A inhibitors for therapeutic targeting of neuroinflammatory diseases: Insights from microsecond MD simulation and MMPBSA analyses.

Tauopathies are a class of nearly 20 neurodegenerative diseases, classified into primary and secondary tauopathies. Alzheimer's disease (AD) is a type of secondary tauopathy in which abnormal phosphorylation of tau proteins takes place, which is linked to the kinase activity of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). Overexpression of DYRK1A hyperphosphorylates the tau protein, leading to its aggregation. Inhibiting DYRK1A activity can be a promising strategy to prevent tau hyperphosphorylation. In this study, we conducted a virtual screening of natural bioactive compounds from the ZINC database to identify potential small-molecule inhibitors of DYRK1A. The analyses revealed two compounds, ZINC08300244 and ZINC08964763, which showed a high binding affinity with DYRK1A and appropriate pharmacokinetic properties. Density functional theory (DFT) analysis of these two compounds was performed, and their stability of interaction with DYRK1A was further analysed by all-atom molecular dynamics (MD) simulations for 1 μs. Analysis of the MD trajectories was also performed using MM/PBSA and per-residue binding free energy decomposition. The results indicated the stable complex formation of DYRK1A with the two selected molecules for DYRK1A inhibition to prevent tau-hyperphosphorylation. This study highlights the use of virtual screening and MD simulations in finding natural product-based inhibitors of DYRK1A, which may lead to the development of novel therapeutic strategies for treating neuroinflammatory diseases.