Structure-guided drug repurposing and dynamics simulation reveal anti-viral candidates for Bourbon virus

The Bourbon virus (BRBV), a recently identified and life-threatening tick-borne pathogen, represents a significant public health concern due to the current absence of approved therapeutics or vaccines. This study aimed to identify potential anti-BRBV candidates through structure-based drug repurposing and virtual screening targeting the viral glycoprotein, a key mediator of host cell entry. The stereochemical quality and integrity of the high-resolution experimental glycoprotein structure (PDB ID: 5ZKX) were validated using PROCHECK and ERRAT, ensuring its appropriateness for drug development applications. Transmembrane prediction using hidden Markov models (TMHMM) confirmed its type I membrane topology. The most conserved and structurally advantageous location for ligand interaction was found to be Pocket 1, out of the five druggable cavities found by binding pocket analysis. Structure-based virtual screening of an FDA-approved library (n = 100) and a natural compound library (n = 1900) was performed using the DrugRep server and Easydock Vina 2.2. Top hits were evaluated for their binding affinity and interaction modes. Pharmacokinetic and toxicity profiles were predicted using SwissADME and ProTox-3.0. The stability of the top ligand-protein complexes was assessed through molecular dynamics (MD) simulations. The top candidates identified were the FDA-approved drugs Rimegepant (- 8.8 kcal/mol) and Dihydroergocornine (- 8.5 kcal/mol), and the natural compounds Avapritinib (- 9.8 kcal/mol) and a triazolyl-benzamide derivative (- 9.0 kcal/mol). All compounds exhibited favorable drug-likeness and ADMET properties, including high gastrointestinal absorption and moderate blood-brain barrier permeability. Toxicity profiling classified most compounds in Class 4 or 5, indicating low to moderate acute toxicity. 2 MD simulations confirmed the stability of the complexes. The computational findings suggest that Rimegepant, Dihydroergocornine, Avapritinib, and the triazolyl-benzamide derivative are promising high-affinity inhibitors of the BRBV glycoprotein. 4They merit further investigation through in vitro and in vivo studies to validate their potential as therapeutic agents against Bourbon virus infection.