Ahmad Fuad, Fazia Adyani and Abdul Hamid, Azzmer Azzar and Saadun, Rafidah
(2017)
Identifying potential inhibitors of human hexokinase II for the development of anti-dengue therapeutics via virtual screening approaches.
In: 4th Asian Regional Conference on Systems Biology, 20-22 Nov 2017, Putrajaya.
Abstract
The human hexokinase II (HK2) has been suggested as a potential therapeutic target
for the development of drugs against dengue virus (DENV) infection. In this paper,
compounds with potential HK2 inhibitory activity have been identified using ligandbased
and structure-based virtual screening approaches. Ligand-based drug design
was performed by using Ultra-Fast Shape Recognition with Atom Types (UFSRAT) and
Ultrafast Shape Recognition with CREDO Atom Types (USRCAT) programmes by
utilising 2-Deoxyglucose (2-DG) as the query molecule, which is a known HK2 inhibitor.
The molecules identified from the programmes showed great similarity to 2-DG with
scores ranged from 0.78-0.85 and 0.88-0.97 for UFSRAT and USRCAT, respectively. The
analogues were docked against the crystal structure of HK2 (PDB ID: 2NZT) in complex
with alpha-D-glucose (GLC) and beta-D-glucose-6-phosphate (BG6) by using AutoDock
Vina programme, on both A and B chains where the active sites were located. The
docking hits for molecules from UFSRAT showed binding energies ranged from -7.1 to -4.8
kcal/mol when docked on chain A, while the hits for chain B showed scores ranged
from -6.7 to -4.8 kcal/mol. On the other hand, the binding energies for molecules from
USRCAT when docked on both A and B chains were similar, which ranged from -7.0 to -
5.2 kcal/mol. The hits bind firmly at the cavities, where both GLC and BG6 were oriented
towards the active sites of HK2. Taken together, this study has successfully discovered
compounds which have potentials as potent inhibitors of HK2, thus pave the path
towards the development of dengue therapeutics.
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