Background:Hexokinase 2 (HKII) is a rate-limiting and the first key enzyme of glycolysis, responsible for the biosynthesis of glucose-6-phospate (G6P) and is up- regulated in dengue virus (DENV) infected cells. During DENV infections, the glycolytic pathway of the host is activated by the pathogens, and inhibition of glycolysis by targeting HKII enzyme can significantly block the infectious DENV production.

Objectives: The main aim of this study was to computer-aided identification of natural bioactive anti-dengue agents that can inhibit the activity of human HKII enzyme.

Methods: A ligand-based pharmacophore model (LBPM) was developed using previously known inhibitors of HKII enzymes to ensure the optimal molecular interactions with the specific target. Virtual screening (VS), molecular docking (MD) and the absorption, distribution, metabolism, excretion, and toxicity (ADMET) approaches were used to identify potential and specific natural human HKII inhibitors.

Result: Based on MD results and binding interaction analysis, four compounds D-Glucose hydrate, (2R,3R,4S,5S)-2,3,4,5,6-Pentahydroxyhexanal, (2S)-2-Amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl) propanehydrazide hydrochloride, (2S)-2-Amino-3-hydroxy-N’, N'-bis[(2,3,4-trihydroxyphenyl)methyl]propanehydrazide were predicted to be the basis for lead optimization. They bind to the active site of human HKII and virtually behave as strong competitive inhibitors.

Interpretation and conclusion: The results demonstrated 4 hits compatible with the active site of HKII enzymes. The current results will be further evaluated in the wet lab by both in vitro and in vivo testing for the development of potential DENV inhibitor.