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.
Macrophage activation is a key event that triggers inflammatory response. The activation is accompanied by metabolic shift such as upregulated glucose metabolism. There are accumulating evidences showing the anti-inflammatory activity of Momordica charantia. However, the effects of M. charantia on inflammatory response and glucose metabolism in activated macrophages have not been fully established. The present study aimed to examine the effect of M. charantia in modulating lipopolysaccharide (LPS)-induced inflammation and perturbed glucose metabolism in RAW264.7 murine macrophages. The results showed that LPS-induced NF-κB (p65) nuclear translocation was inhibited by M. charantia treatment. In addition, M. charantia was found to reduce the expression of inflammatory genes including IL6, TNF-α, IL1β, COX2, iNOS, and IL10 in LPS-treated macrophages. Furthermore, the data showed that M. charantia reduced the expression of GLUT1 and HK2 genes and lactate production (-28%), resulting in suppression of glycolysis. Notably, its effect on GLUT1 gene expression was found to be independent of LPS-induced inflammation. A further experiment also indicated that the bioactivities of M. charantia may be attributed to its key bioactive compound, charantin. Taken together, the study provided supporting evidences showing the potential of M. charantia for the treatment of inflammatory disorders.
This study evaluated the impact of Vernonia amygdalina (VA) on the transcription of key enzymes involved in cellular modulation of glucose in streptozotocin-induced diabetic rats in a bid to understand the possible anti-diabetic mechanism of VA.