Analogues of 2-Deoxyglucose as inhibitor candidates for hexokinase II identified via virtual screening analyses
Dengue fever is one of the major global health issues, yet specific treatment remains vague. The human hexokinase isoform II (HK2) is one of the crucial enzyme for dengue virus (DENV) replication and thus has been suggested as a potential therapeutic target for DENV drug development. In this paper...
| Main Authors: | , , |
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| Format: | Conference or Workshop Item |
| Language: | English |
| Published: |
Kulliyyah of Engineering, International Islamic University Malaysia
2018
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| Subjects: | |
| Online Access: | http://irep.iium.edu.my/70506/ http://irep.iium.edu.my/70506/ http://irep.iium.edu.my/70506/1/70506_Analogues%20of%202-Deoxyglucose%20as%20Inhibitor%20Candidates.pdf |
| Summary: | Dengue fever is one of the major global health issues, yet specific treatment remains vague. The human
hexokinase isoform II (HK2) is one of the crucial enzyme for dengue virus (DENV) replication and thus has
been suggested as a potential therapeutic target for DENV drug development. In this paper, compounds with
potential HK2 inhibitory activity have been identified by using a combination of ligand-based and structurebased
virtual screening approaches. In the initial ligand-based approach, a known HK2 inhibitor, 2-
Deoxyglucose (2-DG) was used as the query molecule, which resulted in the identification of analogues of 2-DG
with scores ranging from 0.739-0.763. 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 Auto Dock
4 programme, on chain B where the active sites were located. The docking hits exhibited binding energy
ranging from -7.63 to -4.98kcal/mol. Six top-ranked compounds which are most similar to 2-DG were
subsequently analysed based on their predicted binding affinity with the catalytic residues (Thr620, Lys621,
Asn656, Lys618, Asp657, Phe604, Asn735, Glu629, Gly710, Gly622 and Glu708), H bond analysis and toxicity
effect. Among the selected top six compounds, only compound 4 (ZINC26898487) is non-toxicant and has shown
good binding energy (-7.63 kcal/mol) relative to 2-DG and contains four H bonds; two with Lys621, one with
Glu629 and another one with is Thr620. Meanwhile, the binding energy of 2-DG itself is -7.40kcal/mol when in
complex with HK2, with two H bonds; one with Lys621 and another one with Glu708. In this drug design
computational studies, compound 4 (ZINC26898487) is suggested to have potentials to inhibit HK2 activity
relative to the known inhibitor (2-DG), thus pave the way towards the discovery of new dengue therapeutics |
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