Multiscale Computational Discovery of an Indole-Based CK2α′ Inhibitor for Huntington's Disease Therapy

Selective inhibition of CK2α′ presents a therapeutic opportunity in Huntington's disease. Using an integrated computational approach, we report the indole-based ligand T-21 as a high-affinity CK2α′ inhibitor. Structurebased docking identified a unique hinge-binding motif. Ensemble MD simulations (triplicate of 100 ns each) demonstrated stable, convergent binding. MM/GBSA calculations yielded strong binding free energies (ΔGbind ≈ −25 kcal/mol), primarily driven by hydrophobic interactions with Met158, Leu40, and Ile111. Quantum mechanical analysis confirmed the structural integrity of the indole scaffold upon binding. With favourable predicted CNS permeability and safety, T-21 represents a promising lead for CK2α′-targeted Huntington's disease therapeutics.