Dengue disease, which is caused by dengue virus (DENV) has been a major worldwide concern, with increased number of cases each year. Currently, there are no specific medications to treat the disease. Hence, there is a dire need to develop novel drugs for disease treatment. Glycolysis is a metabolic pathway that serves as the main source of energy for DENV replication and targeting the pathway is one of the ideal approach to discover new anti-DENV drugs. This paper focuses on the inhibition of human hexokinase isoform 2 (HK2) enzyme, which is one of the important enzymes in glycolysis, in the quest to disrupt DENV replication. In order to search for potential inhibitors, two methods were conducted, which are ligand-based screening and structure-based screening approaches. Docking of Daidzin , which was derived from Kudzu, a Japanese plant, into the active site of HK2 has shown the nearest binding affinity score (-7.94 kcal/mol) to glucose‘s (GLC), which is -8.15 kcal/mol. Meanwhile, Ethyl (2R)-2-[[3-[2-[(4-methylbenzoyl) amino]ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]sulfanyl]butanoate (Ethyl 2(R)), a compound which is the analogue of ((22E, 24R)-6β-methoxyergosta-7, 9(11), 22-triene-3β,5α-diol) or compound 2 from Ganoderma sinense obtained from ligand-based screening was also docked into the binding site of HK2, showing a binding affinity score of -8.43 kcal/mol. Both docking was conducted by using AutoDock4 software at virtual screening phase. These compounds were further analysed in an inhibition assay to determine the effects of these potential naturally-derived inhibitors on the activity of HK2. The outcome from the inhibition studies showed that both compounds exhibited substantial inhibition on the activity of HK2 enzyme, where Daidzin, at 0.5 mM, resulted in HK2 remaining activity of 87.28%, while Ethyl (2R) resulted in 70.09% of HK2 remaining activity at 0.5 mM concentration. The results also indicate that as the concentration of these compounds increased, the percentage of remaining enzyme activity decreased. In conclusion, this study has served as a platform for the development of anti-dengue drugs based on naturally-derived compounds, which is anticipated to be a safer option for dengue treatment.
The human hexokinase isoform II (HKII) is one of the important enzymes for dengue virus (DENV) replication and thus has been suggested as a potential therapeutic target for DENV drug development. In this work, compounds were identified using Ultrafast Shape Recognition with CREDO Atom Types (USRCAT) by utilizing both HKII’s substrate and product; alpha-D-glucose (GLC) and beta-D-glucose-6-phosphate (BG6), as well as a known HKII’s inhibitor, 2-deoxyglucose (2DG), as the query molecules. The analogues of the three query molecules were subsequently docked against the HKII’s crystal structure (PDB ID: 2NZT) by using Auto Dock 4 program on Chain B, where the active sites and strong bonds were located. Among the top-ranked compounds, Compound 4 (ZINC26898487), which was the most similar to 2DG, showed the best binding energy (-7.63 kcal/mol) and contained two H bonds. Compound 9 (ZINC16930948), an analogue of GLC emerged as the best inhibitor candidate because it had six H bonds. Similarly, among the molecules similar to BG6, Compound 14 (ZINC4403351) had been suggested as a potential inhibitor because it contained four strong H bonds. All compounds were predicted to be non-toxic, based on Toxicity Estimation Software Tool (TEST) analysis. By providing these valuable findings, this study has paved the way for the discovery of compounds that should be further tested for the development of anti-dengue drugs.
Cofactor-independent phosphoglycerate mutase has been proposed as a therapeutic target for the treatment of
trypanosomatid diseases. In this paper, we report the identification of compounds that could potentially be developed as
selective inhibitors of cofactor-independent phosphoglycerate mutase from Leishmania mexicana (LmiPGAM). Virtual
screening was used in this search, as well as compounds identified by high-throughput screening. A ligand-based virtual
screen programme, ultra fast shape recognition with atom types (UFSRAT), was used to screen for compounds resembling
the substrate/product, before a structure-based approach was applied using AutoDock 4 and AutoDock Vina in a consensus
docking scheme. In this way eight selected compounds were identified. In addition, three compounds from the Library of
Pharmacologically Active Compounds (LOPAC) were selected from the published results of high-throughput screening of
this library. The inhibitory effects of these compounds were tested at a fixed concentration of 1 mM. The results showed
that seven compounds inhibited LmiPGAM activity and of these, two compounds (one each from high-throughput and
virtual screening) showed substantial inhibition (i.e. 14% and 49% remaining activity, respectively). Taken together, the
findings from this study indicate that these compounds have potential as novel inhibitors that specifically target LmiPGAM.