Analogues of 2-Deoxyglucose as inhibitor candidates for hexokinase II identified via virtual screening analyses

Tanbin, Suriyea and Ogu Salim, Nurhainis and Ahmad Fuad, Fazia Adyani (2018) Analogues of 2-Deoxyglucose as inhibitor candidates for hexokinase II identified via virtual screening analyses. In: 5th International Conference on Biotechnology Engineering (ICBioE 2018), 19th-20th September 2018, Kuala Lumpur.

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Abstract

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

Item Type:	Conference or Workshop Item (Slide Presentation)
Additional Information:	7200/70506
Uncontrolled Keywords:	Dengue, glycolysis, Human Hexokinase II (HK2); 2-Deoxyglucose (2-DG); virtual screening; toxicity test
Subjects:	T Technology > TP Chemical technology > TP248.13 Biotechnology
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Engineering Kulliyyah of Engineering > Department of Biotechnology Engineering
Depositing User:	Dr Fazia Adyani Ahmad Fuad
Date Deposited:	27 Feb 2019 13:43
Last Modified:	17 Mar 2022 16:16
URI:	http://irep.iium.edu.my/id/eprint/70506

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