Zika virus (ZIKV) is a flavivirus transmitted by mosquitoes, causing neurological disorders and congenital malformations. RNA-dependent RNA polymerase (RdRp) is one of its essential enzymes and a promising drug target for antiviral therapy due to its involvement in the growth and multiplication of the virus. In this study, we conducted a QSAR-based chemical library screening from the Meliaceae family to identify potential RdRp inhibitors. The QSAR model was built using the known inhibitors of RdRp NS5 of ZIKV and their biological activity (EC50), along with the structural and chemical characteristics of the compounds. The top two hit compounds were selected from QSAR screening for further analysis using molecular docking to evaluate their binding energies and intermolecular interactions with RdRp, including the critical residue Trp
In this study, a comprehensive investigation of a set of phytochemicals to identify potential inhibitors for the Forkhead box protein M1 (FOXM1) was conducted. FOXM1 is overexpressed in glioblastoma (GBM) cells and plays a crucial role in cell cycle progression, proliferation, and invasion. FOXM1 inhibitors have shown promising results in preclinical studies, and ongoing clinical trials are assessing their efficacy in GBM patients. However, there are limited studies on the identification of novel compounds against this attractive therapeutic target. To address this, the NPACT database containing 1,574 phytochemicals was used, employing a hierarchical multistep docking approach, followed by an estimation of relative binding free energy. By fixing user-defined XP-dock and MM-GBSA cut-off scores of −6.096 and −37.881 kcal/mol, the chemical space was further narrowed. Through exhaustive analysis of molecular binding interactions and various pharmacokinetics profiles, we identified four compounds, namely NPACT00002, NPACT01454, NPACT00856, and NPACT01417, as potential FOXM1 inhibitors. To assess the stability of protein-ligand binding in dynamic conditions, 100 ns Molecular dynamics (MD) simulations studies were performed. Furthermore, Molecular mechanics with generalized Born and surface area solvation (MM-GBSA) based binding free energy estimations of the entire simulation trajectories revealed a strong binding affinity of all identified compounds towards FOXM1, surpassing that of the control drug Troglitazone. Based on extensively studied multistep docking approaches, we propose that these molecules hold promise as FOXM1 inhibitors for potential therapeutic applications in GBM. However, experimental validation will be necessary to confirm their efficacy as targeted therapies.
The objective of the present study is to evaluate the pharmacological actions of earlier reported metabolites (1-5), and semi-synthetic analogs (4a-e) from acetone extract of Ramalina leiodea. The Acetone extract of Ramalina leiodea were screened for antioxidant, anti-inflammatory, anticancer, and acute toxicity studies. The antioxidant results exhibited that compound 4e showed effective inhibitory ability against ferric ions, 2,2-diphenyl-1-picrylhydrazyl and superoxide free radicals with 50 % inhibition value of 28.50, 27.0, and 25.0 μg/ml, respectively. Also, among all the samples, 4e revealed good inhibition of albumin denaturation of 105 μg/ml (IC50 value). Additionally, the median lethal dosage of acetone extract of Ramalina leiodea was observed to be above 2000 mg/Kg body weight. Also, the in vivo antiinflammatory studies of acetone extract of Ramalina leiodea exhibited a noticeable reduction of edema in rat paw at both low and high dosage when compared to indomethacin. From the sulforhodamine B assay, it is concluded that 2 and 4b displayed a noteworthy degree of specificity against tested series of cell lines. On the other hand, all tested samples displayed a low degree of specificity against normal cells. To conclude, Ramalina leiodea could be the best source for bioactive agents for the management of oxidative stress, inflammation, and cancer.
Introduction: The mixed flavonoid supplement (MFS) [Trimethoxy Flavones (TMF) + epigallocatechin-3-gallate (EGCG)] can be used to suppress inflammatory ulcers as an ethical medicine in Ayurveda. The inflammation of the rectum and anal regions is mostly attributed to nuclear factor kappa beta (NF-κB) signaling. NF-κB stimulates the expression of matrix metalloproteinase (MMP9), inflammatory cytokines tumor necrosis factor (TNF-α), and interleukin-1β (IL-1β). Although much research targeted the NF-κB and MMP9 signaling pathways, a subsequent investigation of target mediators in the inflammatory ulcer healing and NF-κB pathway has not been done. Methods: The docking studies of compounds TMF and EGCG were performed by applying PyRx and available software to understand ligand binding properties with the target proteins. The synergistic ulcer healing and anti-arthritic effects of MFS were elucidated using dextran sulfate sodium (DSS)-induced colon ulcer in Swiss albino rats. The colon mucosal injury was analyzed by colon ulcer index (CUI) and anorectic tissue microscopy. The IL-1β, tumor necrosis factor (TNF-α), and the pERK, MMP9, and NF-κB expressions in the colon tissue were determined by ELISA and Western blotting. RT-PCR determined the mRNA expression for inflammatory marker enzymes. Results: The docking studies revealed that EGCG and TMF had a good binding affinity with MMP9 (i.e., -6.8 and -6.0 Kcal/mol) and NF-kB (-9.4 and 8.3 kcal/mol). The high dose MFS better suppressed ulcerative colitis (UC) and associated arthritis with marked low-density pERK, MMP9, and NF-κB proteins. The CUI score and inflammatory mediator levels were suppressed with endogenous antioxidant levels in MFS treated rats. Conclusion: The MFS effectively unraveled anorectic tissue inflammation and associated arthritis by suppressing NF-κB-mediated MMP9 and cytokines.
'%3e%3ccircle r='20' fill='%23008'/%3e%3ccircle r='17.5' fill='%23fff'/%3e%3ccircle r='3.5' fill='%23008'/%3e%3cg id='d'%3e%3cg id='c'%3e%3cg id='b'%3e%3cg id='a' fill='%23008'%3e%3ccircle r='.875' transform='rotate(7.5 -8.75 133.5)'/%3e%3cpath d='M0 17.5.6 7 0 2l-.6 5L0 17.5z'/%3e%3c/g%3e%3cuse xlink:href='%23a' transform='rotate(15)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(30)'/%3e%3c/g%3e%3cuse xlink:href='%23c' transform='rotate(60)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='rotate(120)'/%3e%3cuse xlink:href='%23d' transform='rotate(-120)'/%3e%3c/g%3e%3c/svg%3e)