Structure-based repurposing of antimalarial drugs to inhibit the RNA-dependent RNA polymerase of dengue virus

Abstract

Introduction: Dengue fever is becoming a global health emergency, being the most widespread mosquito-borne viral disease, putting half the world population at risk of infection. Dengue virus (DENV), the causative agent of the disease, is classified into four serotypes (DENV-1 – DENV-4), each associated with fever and dengue shock syndrome. Currently, no antiviral drugs are approved for the disease; treatments are based on supportive care. This study follows a comprehensive structure-based virtual screening approach to screen a collection of approved antimalarial drugs for binding efficiency and inhibitory potential against DENV RNA-dependent RNA polymerase (DENV RdRp). Method: We retrieved thirty-one (31) approved antimalarial drugs from published literature. This was followed by downloading the three-dimensional structures (3D) of each drug from the PubChem website and the crystal structure of the protein (PDB ID: 2J7W) from the Protein Data Bank. We computed the root mean square deviation (RMSD) to validate the docking study. The molecular docking and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) evaluation were performed using the Maestro Schrodinger software user interface. The Maestro’s molecular visualisation tool was utilised to perform a post-docking analysis for each of the top drug candidates Result: The computed RMSD for the redocked cocrystallized ligand was 2.0 Å. The docking scores for the top 5 drug candidates were Chloroquine (-4.109 kcal/mol), 3-hydroxyquinine (-4.01 kcal/mol), Tetracycline (-6.494 kcal/mol), Artesunate (-4.4 kcal/mol) and Chlorproguanil (-4.021 kcal/mol). The MMGBSA (dG bind) for the top five drug candidates were Chloroquine (-40.66 kcal/mol), 3-hydroxyquinine (-36.95 kcal/mol), Tetracycline (-36.69 kcal/mol), Artesunate (-35.17 kcal/mol), and Chlorproguanil (-34.18 kcal/mol). The post-docking analysis revealed considerable intermolecular interactions between the drug candidates and protein. Conclusion: Several clinically approved antimalarial agents, including chloroquine, 3-hydroxyquinine, tetracycline, and artesunate, demonstrated favourable binding affinities and stable interactions with catalytically essential residues of the enzyme (DENV RdRp). These interactions suggest potential inhibitory effects on viral replication consistent with previous in vitro and in vivo observations. Future studies should integrate molecular dynamics simulations, enzymatic inhibition assays, and animal model testing to confirm their antiviral efficacy and clarify the molecular basis of NS5 inhibition.