Virtual Screening for Possible Allosteric Inhibitors of Dengue RNA-dependent RNA polymerase (RdRp)

Abstract

Background and Objective: Virtual screening involves the docking of databases containing the structures of small molecules into a region of interest in silico and the scoring of ligands according to their predicted target site interactions. In this study, virtual screening was employed for the identification of possible inhibitors for the “cavity B” of the Dengue RNA-dependent RNA polymerase (RdRp). The target enzyme was chosen because of its essentiality for the vitality of the virus, its highly conserved sequence and structure not just among Dengue serotypes but also among the flaviviruses, and its reported absence in human cells.
Methodology: LibDock was used for molecular docking of the top hits from virtual screening, resulting in the identification of eight different compounds with comparable binding energies. The interactions between the ligands and the binding site of the enzyme were subsequently analyzed using ligand binding patterns and ligand interaction diagrams.
Results and Conclusion: All identified compounds came from the MEGx database, a library of natural products. The top compound with the highest binding energy of -198.813 kcal/mol was Compound498 (1-O-{2,4-Dihydroxy-6-[(E)-2-phenylvinyl]benzoyl}hexopyranose). Furthermore, Lys329, a residue found in “cavity B” played a significant role in the binding of all ligands via hydrogen-bonding, charged interactions and/or pi-cation interactions. The compounds identified in this study may provide access to highly desired anti-dengue drug.
Key words: virtual screening, dengue infection, dengue RNA-dependent RNA polymerase (dengue RdRp), structure based pharmacophore, molecular docking