Detailed in silico Evaluation of WNV Proteins: Dynamic and Thermodynamic Insights into Doravirine as a Potential...

The West Nile Virus (WNV) remains a global health problem, necessitating the identification of effective antiviral strategies. This study aimed to identify potential druggable targets for WNV and assess the repurposing of three FDA-approved antivirals - remdesivir, rilpivirine, and doravirine - through comprehensive in silico evaluations.

Through molecular docking, molecular dynamics simulations (MDs), and Molecular Mechanics Generalized Born/Surface Area (MM-GBSA) free energy calculations, we assessed the stability, binding affinity, and thermodynamic profiles of the drug-protein complexes, focusing on the core protein, nonstructural protein NS3 serine protease, and two domains of nonstructural protein NS5: RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase).

Doravirine showed the most favorable and stable interactions across multiple targets. Specifically, it exhibited strong and persistent binding within the C-terminal tunnel and N-terminal hydrophobic pocket of the core protein, as well as at the KDKE motif and SAH-binding site of the NS5 MTase domain. Triplicate MD simulations and residue-level fluctuation analyses further confirm doravirine's stability and consistent interaction patterns in all binding sites, highlighting its potential as a promising candidate for WNV inhibition with multitarget activity.

These findings provide in silico evidence supporting doravirine as a promising multitarget inhibitor of WNV, warranting further investigation for its repurposing for WNV treatment.