Current Issue : January - March Volume : 2017 Issue Number : 1 Articles : 5 Articles
Aldosterone synthase (CYP11B2) is a key enzyme for the biosynthesis of aldosterone, which plays a significant role for the regulation\nof blood pressure. Excess aldosterone can cause the dysregulation of the renin-angiotensin-aldosterone system (RAAS) and lead\nto hypertension. Therefore, research and development of CYP11B2 inhibitor are regarded as a novel approach for the treatment of\nhypertension. In this study, the pharmacophore models of CYP11B2 inhibitors were generated and the optimal model was used\nto identify potential CYP11B2 inhibitors from the Traditional Chinese Medicine Database (TCMD, Version 2009). The hits were\nfurther refined by molecular docking and the interactions between compounds and CYP11B2 were analyzed. Compounds with\nhigh Fitvalue, high docking score, and expected interactions with key residues were selected as potential CYP11B2 inhibitors. Two\nmost promising compounds, ethyl caffeate and labiatenic acid, with high Fitvalue and docking score were reserved for molecular\ndynamics (MD) study. All of them have stability of ligand binding which suggested that they might perform the inhibitory effect\non CYP11B2. This study provided candidates for novel drug-like CYP11B2 inhibitors by molecular simulation methods for the\nhypertension treatment....
Background: Parkinsonââ?¬â?¢s disease is a neurodegenerative disorder associated with oxidative stress and glutathione\ndepletion. The induction of cellular glutathione levels by exogenous molecules is a promising neuroprotective\napproach to limit the oxidative damage that characterizes Parkinsonââ?¬â?¢s disease pathophysiology. Dithiolethiones, a\nclass of sulfur-containing heterocyclic molecules, are known to increase cellular levels of glutathione; however, limited\ninformation is available regarding the influence of dithiolethione structure on activity. Herein, we report the design,\nsynthesis, and pharmacological evaluation of a further series of dithiolethiones in the SH-SY5Y neuroblastoma cell\nline.\nResults: Our structureââ?¬â??activity relationships data show that dithiolethione electronic properties, given as Hammett\nÃÆ?p constants, influence glutathione induction activity and compound toxicity. The most active glutathione inducer\nidentified, 6a, dose-dependently protected cells from 6-hydroxydopamine toxicity. Furthermore, the protective\neffects of 6a were abrogated by the inhibitor of glutathione synthesis, buthionine sulfoximine, confirming the importance\nof glutathione in the protective activities of 6a.\nConclusions: The results of this study further delineate the relationship between dithiolethione chemical structure\nand glutathione induction. The neuroprotective properties of analog 6a suggest a role for dithiolethiones as potential\nantiparkinsonian agents....
The increasing size of datasets in drug discovery makes it challenging to build robust and accurate predictive models\nwithin a reasonable amount of time. In order to investigate the effect of dataset sizes on predictive performance and\nmodelling time, ligand-based regression models were trained on open datasets of varying sizes of up to 1.2 million\nchemical structures. For modelling, two implementations of support vector machines (SVM) were used. Chemical\nstructures were described by the signatures molecular descriptor. Results showed that for the larger datasets, the\nLIBLINEAR SVM implementation performed on par with the well-established libsvm with a radial basis function kernel,\nbut with dramatically less time for model building even on modest computer resources. Using a non-linear kernel\nproved to be infeasible for large data sizes, even with substantial computational resources on a computer cluster. To\ndeploy the resulting models, we extended the Bioclipse decision support framework to support models from LIBLINEAR\nand made our models of logD and solubility available from within Bioclipse....
In this study, in silico approaches, including multiple QSAR modeling, structural similarity\nanalysis, and molecular docking, were applied to develop QSAR classification models as a fast\nscreening tool for identifying highly-potent ABCA1 up-regulators targeting LXR�² based on a series\nof new flavonoids. Initially, four modeling approaches, including linear discriminant analysis,\nsupport vector machine, radial basis function neural network, and classification and regression\ntrees, were applied to construct different QSAR classification models. The statistics results indicated\nthat these four kinds of QSAR models were powerful tools for screening highly potent ABCA1\nup-regulators. Then, a consensus QSAR model was developed by combining the predictions from\nthese four models. To discover new ABCA1 up-regulators at maximum accuracy, the compounds in\nthe ZINC database that fulfilled the requirement of structural similarity of 0.7 compared to known\npotent ABCA1 up-regulator were subjected to the consensus QSAR model, which led to the discovery\nof 50 compounds. Finally, they were docked into the LXR�² binding site to understand their role\nin up-regulating ABCA1 expression. The excellent binding modes and docking scores of 10 hit\ncompounds suggested they were highly-potent ABCA1 up-regulators targeting LXR�². Overall, this\nstudy provided an effective strategy to discover highly potent ABCA1 up-regulators....
Background: Influenza is historically an ancient disease that causes annual epidemics and, at irregular intervals,\npandemics. At present, the first-line drugs (oseltamivir and zanamivir) donââ?¬â?¢t seem to be optimistic due to the spontaneously\narising and spreading of oseltamivir resistance among influenza virus. Pogostemon cablin (Blanco) Benth.\n(P. cablin) is an important traditional Chinese medicine herb that has been widely used for treatment on common\ncold, nausea and fever. In our previous study, we have identified an extract derived from P. cablin as a novel selective\nneuraminidase (NA) inhibitor.\nResults: A series of polyphenolic compounds were isolated from P. cablin for their potential ability to inhibit neuraminidase\nof influenza A virus. Two new octaketides (1, 2), together with other twenty compounds were isolated from\nP. cablin. These compounds showed better inhibitory activity against NA. The significant potent compounds of this\nseries were compounds 2 (IC50 = 3.87 Ã?± 0.19 Ã?¼ mol/ml), 11, 12, 14, 15, 19 and 20 (IC50 was in 2.12 to 3.87 Ã?¼ mol/\nml), which were about fourfold to doubled less potent than zanamivir and could be used to design novel influenza\nNA inhibitors, especially compound 2, that exhibit increased activity based on these compounds. With the help of\nmolecular docking, we had a preliminary understanding of the mechanism of the two new compounds (1ââ?¬â??2)ââ?¬â?¢ NA\ninhibitory activity.\nConclusions: Fractions 6 and polyphenolic compounds isolated from fractions 6 showed higher NA inhibition\nthan that of the initial plant exacts. The findings of this study indicate that polyphenolic compounds and fractions 6\nderived from P. cablin are potential NA inhibitors. This work is one of the evidence that P. cablin has better inhibitory\nactivity against influenza, which not only enriches the compound library of P. cablin, but also facilitates further development\nand promises its therapeutic potential for the rising challenge of influenza diseases....
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