Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling

Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174

Protective role of Mas Cotek (Ficus deltoidea) against the toxic effects of bisphenol A on morphology and sex steroid receptor expression in the rat uterus

Background: Numerous scientific studies have found that young women are at a high risk of reproductive infertility due to their routine exposure to numerous bisphenol A (BPA) products. This risk is highly associated with the production of reactive oxygen species from BPA products. Ficus deltoidea, which has strong antioxidant properties, was selected as a potential protective agent to counter the detrimental effects of BPA in the rat uterus. Methods: Female Sprague–Dawley rats were allocated into four groups (n = 8) as follows: (i) the Normal Control group (NC), (ii) the BPA-exposed group (PC), (iii) the group concurrently treated with BPA and F. deltoidea (FC) and (iv) the group treated with F. deltoidea alone (F). Results: After 6 weeks of concurrent treatment with F. deltoidea, uterine abnormalities in the BPA-exposed rats showed a significant improvement. Specifically, the size of stromal cells increased; interstitial spaces between stromal cells expanded; the histology of the glandular epithelium and the myometrium appeared normal and mitotic figures were present. The suppressive effects of BPA on the expression levels of sex steroid receptors (ERα and ERβ) and the immunity gene C3 were significantly normalised by F. deltoidea treatment. The role of F. deltoidea as an antioxidant agent was proven by the significant reduction in malondialdehyde level in BPA-exposed rats. Moreover, in BPA-exposed rats, concurrent treatment with F. deltoidea could normalise the level of the gonadotropin hormone, which could be associated with an increase in the percentage of rats with a normal oestrous cycle. Conclusion: F. deltoidea has the potential to counter the toxic effects of BPA on the female reproductive system. These protective effects might be due to the phytochemical properties of F. deltoidea. Therefore, future study is warranted to identify the bioactive components that contribute to the protective effects of F. deltoidea

Protective role of Ficus deltoidea against BPA-induced impairments of the follicular development, estrous cycle, gonadotropin and sex steroid hormones level of prepubertal rats

Ficus deltoideais one of the well-known medicinal plants in Malaysia that is traditionally used by the Malay community totreat various ailments and for maintenance of female reproductive health. The objective of this study is to evaluate thepotential protective roles ofFicus deltoideaagainst BPA-induced toxicity of the pituitary-ovarian axis in pre-pubertal femalerats. In this study, four groups of pre-pubertal female Sprague Dawley rats were administered with the followings by oralgavage for a period of six weeks: NC (negative control- treated with vehicle), PC (positive control-treated with BPA at 10 mg/kg/BW), F (treated withFicus deltoideaat 100 mg/kg/BW, then exposed to BPA at 10 mg/kg/BW) and FC (Ficus deltoideacontrol - treated withFicus deltoideaat 100 mg/kg/BW). Daily vaginal smear, ovarian follicular development as well asgonadotropin and sexual-steroid hormone levels were determined. The findings showed thatFicus deltoideademonstratedpreventive role against BPA-induced toxicity on the ovaries. This was evident bythe increased percentage of rats withnormal estrous cycle, qualitatively reduced number of atretic follicles (as observed in histopathological examination) andnormalization of the gonadotropins hormone (FSH) and sexual steroid hormone (progesterone) levels. In conclusion,Ficusdeltoideahas the capability to prevent the effects of BPA toxicity in the hypothalamus-pituitary-gonadal axis of prepubertalfemale reproductive system, possibly due to its variety ofphytochemical properties. Therefore, these findingsstrongly support the traditional belief that this medicinal plant is beneficial as daily dietary supplement forthe maintenance of female reproductive health

A preliminary study on the impact of UCK2 knockdown in DLD-1 colorectal cells treated with DHODH inhibitor

Brequinar sodium (BQR) is a well-studied inhibitor of the dihydroorotate dehydrogenase (DHODH) enzyme. Both the DHODH and uridine-cytidine kinase 2 (UCK2) enzymes have been reported to be over-expressed in cancer cells to maintain the cells high demand for DNA and RNA for their proliferation. In this study, we aim to further sensitize cells to the effects of BQR by knocking down the UCK2 activity. In DLD-1 UCK2 knockdown cells, no change in the sensitivity of cells to BQR was observed. Uridine is known to reverse the anti-proliferative effect of DHODH inhibitors via the salvage pathway. We observed abrogation of approximately 30% of the uridine reversal effect in UCK2 knockdown cells compared to the wild type cells. Our finding indicates that the loss of UCK2 activity in the salvage pathway did not enhance the BQR-mediated cell proliferation inhibition but it abrogates the uridine reversal in the cells

Structures and binding specificity of galactose- and mannose-binding lectins from champedak: differences from jackfruit lectins

Galactose-binding and mannose-binding lectins from the champedak fruit, which is native to South-east Asia, exhibit useful potential clinical applications. The specificity of the two lectins for their respective ligands allows the detection of potential cancer biomarkers and monitoring of the glycosylated state of proteins in human serum and/or urine. To fully understand and expand the use of these natural proteins, their complete sequences and crystal structures are presented here, together with details of sugar binding