Current Issue : October - December Volume : 2020 Issue Number : 4 Articles : 5 Articles
Novel drug discovery is time-consuming, costly, and a high-investment process due to the\nhigh attrition rate. Therefore, many trials are conducted to reuse existing drugs to treat pressing\nconditions and diseases, since their safety profiles and pharmacokinetics are already available. Drug\nrepositioning is a strategy to identify a new indication of existing or already approved drugs, beyond\nthe scope of their original use. Various computational and experimental approaches to incorporate\navailable resources have been suggested for gaining a better understanding of disease mechanisms and\nthe identification of repurposed drug candidates for personalized pharmacotherapy. In this review,\nwe introduce publicly available databases for drug repositioning and summarize the approaches\ntaken for drug repositioning. We also highlight and compare their characteristics and challenges,\nwhich should be addressed for the future realization of drug repositioning....
Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising\ntarget in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors\nare currently known, identification of their novel chemotypes attracts considerable interest. In this\nstudy, the molecular docking and machine learning-based virtual screening techniques combined\nwith the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity)\nprofile prediction and molecular dynamics simulations were applied to a subset of the ZINC database\ncontaining about 1.7 M commercially available compounds. Out of seven candidate compounds\nbiologically evaluated in vitro for their inhibition of the TNKS2 enzyme using immunochemical\nassay, two compounds have shown a decent level of inhibitory activity with the IC50 values of\nless than 10 nM and 10 microM. Relatively simple scores based on molecular docking or MM-PBSA\n(molecular mechanics, Poisson-Boltzmann, surface area) methods proved unsuitable for predicting\nthe effect of structural modification or for accurate ranking of the compounds based on their binding\nenergies. On the other hand, the molecular dynamics simulations and Free Energy Perturbation (FEP)\ncalculations allowed us to further decipher the structure-activity relationships and retrospectively\nanalyze the docking-based virtual screening performance. This approach can be applied at the\nsubsequent lead optimization stages....
Leukotriene B4 (LTB4) is a potent, proinflammatory lipid mediator implicated in the\npathologies of an array of inflammatory diseases and cancer. The biosynthesis of LTB4 is regulated\nby the leukotriene A4 hydrolase (LTA4H). Compounds capable of limiting the formation of LTB4,\nthrough selective inhibition of LTA4H, are expected to provide potent anti-inflammatory and\nanti-cancer agents. The aim of the current study is to obtain potential LTA4H inhibitors using\ncomputer-aided drug design. A hybrid 3D structure-based pharmacophore model was generated\nbased on the crystal structure of LTA4H in complex with bestatin. The generated pharmacophore\nwas used in a virtual screen of the Maybridge database. The retrieved hits were extensively filtered,\nthen docked into the active site of the enzyme. Finally, they were consensually scored to yield five hits\nas potential LTA4H inhibitors. Consequently, the selected hits were purchased and their biological\nactivity assessed in vitro against the epoxide hydrolase activity of LTA4H. The results were very\npromising, with the most active compound showing 73.6% inhibition of the basal epoxide hydrolase\nactivity of LTA4H. The results from this exploratory study provide valuable information for the design\nand development of more potent and selective inhibitors....
Complications due to influenza are often associated with inflammation with excessive\nrelease of cytokines. The bulbs of Fritillariae thunbergii (FT) have been traditionally used to\ncontrol airway inflammatory diseases, such as bronchitis and pneumonia. To elucidate active\ncompounds, the targets, and underlying mechanisms of FT for the treatment of influenza-induced\ninflammation, systems biology was employed. Active compounds of FT were identified through\nthe TCMSP database according to oral bioavailability (OB) and drug-likeness (DL) criteria.\nOther pharmacokinetic parameters, Caco-2 permeability (Caco-2), and drug half-life (HL) were\nalso identified. Biological targets of FT were retrieved from DrugBank and STITCH databases,\nand target genes associated with influenza, lung, and spleen inflammation were collected from\nDisGeNET and NCBI databases. Compound-disease-target (C-D-T) networks were constructed and\nmerged using Cytoscape. Target genes retrieved from the C-D-T network were further analyzed with\nGO enrichment and KEGG pathway analysis. In our network, GO and KEGG results yielded two\ncompounds (beta-sitosterol (BS) and pelargonidin (PG)), targets (PTGS1 (COX-1) and PTGS2 (COX-2)),\nand pathways (nitric oxide, TNF) were involved in the inhibitory effects of FT on influenza-associated\ninflammation. We retrieved the binding affnity of each ligand-target, and found that PG and COX-1\nshowed the strongest binding affnity among four binding results using a molecular docking method.\nWe identified the potential compounds and targets of FT against influenza and suggest that FT is an\nimmunomodulatory therapy for influenza-associated inflammation....
Withania coagulans (W. coagulans) is well-known in herbal medicinal systems for its high\nbiological potential. Different parts of the plant are used against insomnia, liver complications,\nasthma, and biliousness, as well as it is reported to be sedative, emetic, diuretic, antidiabetic\nantimicrobial, anti-inflammatory, antitumor, hepatoprotective, antihyperglycemic, cardiovascular,\nimmuno-suppressive and central nervous system depressant. Withanolides present in W. coagulans\nhave attracted an immense interest in the scientific field due to their diverse therapeutic applications.\nThe current study deals with chemical and biological evaluation of chloroform, and n-butanol fractions\nof W. coagulans. The activity-guided fractionation of both extracts via multiple chromatographic\nsteps and structure elucidation of pure isolates using spectroscopies (NMR, mass spectrometry,\nFTIR and UV-Vis) led to the identification of a new withanolide glycoside, withacogulanoside-B\n(1) from n-butanol extract and five known withanolides from chloroform extract [withanolid J (2),\ncoagulin E (3), withaperuvin C (4), 27-hydroxywithanolide I (5), and ajugin E (6)]. Among the tested\ncompounds, compound 5 was the most potent-glucosidase inhibitor with IC50 = 66.7 3.6 microM,\nfollowed by compound 4 (IC50: 407 4.5 microM) and compound 2 (IC50: 683 0.94 microM), while no\nantiglycation activity was observed with the six isolated compounds. Molecular docking was used\nto predict the binding potential and binding site interactions of these compounds as -glucosidase\ninhibitors. Consequently, this study provides basis to discover specific antidiabetic compounds from\nW. coagulans....
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