In silico drug repurposing of beta-blockers against HSV-1 TK using molecular docking and molecular dynamics simulations.

Herpes simplex virus type 1 (HSV-1) is highly prevalent, but emerging drug-resistant strains against nucleoside analogs like acyclovir demand novel therapeutics. This study employed an in silico drug repurposing approach to screen 41 beta-blockers as potential non-nucleoside inhibitors targeting HSV-1 thymidine kinase (TK). Molecular docking, 100 ns molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, per-residue energy decomposition, and ADMET analysis were performed. Docking results revealed several beta-blockers surpassed acyclovir (-5.20 kcal/mol) in binding energy, with bopindolol emerging as the top candidate (-9.32 kcal/mol). Interaction analysis showed bopindolol forms stable hydrogen bonds with Gln125, Arg163, and Arg222, alongside stabilizing hydrophobic interactions. MD simulations confirmed the structural stability of the bopindolol-HSV-1 TK complex, evidenced by stable RMSD, low residue fluctuations, persistent hydrogen bonding, and consistent protein compactness. MM/GBSA calculations yielded a favourable delta G binding of -53.08 ± 3.57 kcal/mol. Energy decomposition indicated binding is driven by van der Waals and electrostatic interactions, with key contributions from Arg222, Tyr172, Met128, and Gln125. Furthermore, ADMET analysis demonstrated favourable pharmacokinetic properties for bopindolol. Overall, bopindolol represents a promising non-nucleoside inhibitor scaffold targeting HSV-1 TK, warranting further experimental validation.