Current Issue : July - September Volume : 2016 Issue Number : 3 Articles : 5 Articles
Cholesteryl ester transfer protein (CETP) is responsible for the transfer of cholesteryl esters from antiatherogenic HDLs to proatherogenic apolipoprotein B. A deficiency of CETP is associated with increased HDL levels and decreased LDL levels, a profile that is typically antiatherogenic. Inhibition of CETP may act as potential target for antihyperlipidemic drug design. The current manuscript deals with the 3D QSAR, pharmacophore identification of some reported CETP inhibitors....
Development of homology model for human Phosphodiesterase 3A has been targeted. Homology-modeling was utilized to generate a reliable molecular model of the human PDE3A based on the crystal structure of PDE3B using biopredicta module of Vlife MDS 4.3 and validated using online servers like procheck. In this work, developed a new homology model of human PDE3A enzyme and validated using various parameters like ramchandran plot and anolea plots which indicated that the developed model has good quality. Developed model of PDE3A can be useful for the development of novel human PDE3A inhibitors as potential vascular smooth muscle relaxants for treatment of various cardiovascular diseases....
Background: The disposition of a pharmaceutical compound within an organism, i.e. its Absorption, Distribution,\nMetabolism, Excretion, Toxicity (ADMET) properties and adverse effects, critically affects late stage failure of drug candidates\nand has led to the withdrawal of approved drugs. Computational methods are effective approaches to reduce\nthe number of safety issues by analyzing possible links between chemical structures and ADMET or adverse effects,\nbut this is limited by the size, quality, and heterogeneity of the data available from individual sources. Thus, large,\nclean and integrated databases of approved drug data, associated with fast and efficient predictive tools are desirable\nearly in the drug discovery process.\nDescription: We have built a relational database (IDAAPM) to integrate available approved drug data such as drug\napproval information, ADMET and adverse effects, chemical structures and molecular descriptors, targets, bioactivity\nand related references. The database has been coupled with a searchable web interface and modern data analytics\nplatform (KNIME) to allow data access, data transformation, initial analysis and further predictive modeling. Data were\nextracted from FDA resources and supplemented from other publicly available databases. Currently, the database\ncontains information regarding about 19,226 FDA approval applications for 31,815 products (small molecules and biologics)\nwith their approval history, 2505 active ingredients, together with as many ADMET properties, 1629 molecular\nstructures, 2.5 million adverse effects and 36,963 experimental drug-target bioactivity data.\nConclusion: IDAAPM is a unique resource that, in a single relational database, provides detailed information on\nFDA approved drugs including their ADMET properties and adverse effects, the corresponding targets with bioactivity\ndata, coupled with a data analytics platform. It can be used to perform basic to complex drug-target ADMET or\nadverse effects analysis and predictive modeling. IDAAPM is freely accessible at http://idaapm.helsinki.fi and can be\nexploited through a KNIME workflow connected to the database....
Bone anabolic agents promoting bone formation and rebuilding\ndamaged bones would ideally overcome the limitations of antiresorptive\ntherapy, the current standard prescription for\nosteoporosis. However, the currently prescribed parathyroid\nhormone (PTH)-based anabolic drugs present limitations and\nadverse effects including osteosarcoma during long-term use. Also,\nthe antibody-based anabolic drugs that are currently being developed\npresent the potential limits in clinical application typical of\nmacromolecule drugs. We previously identified that CXXC5 is a\nnegative feedback regulator of the Wnt/b-catenin pathway via its\ninteraction with Dishevelled (Dvl) and suggested the Dvlââ?¬â??CXXC5\ninteraction as a potential target for anabolic therapy of osteoporosis.\nHere, we screened small-molecule inhibitors of the Dvlââ?¬â??CXXC5\ninteraction via a newly established in vitro assay system. The\nscreened compounds were found to activate the Wnt/b-catenin\npathway and enhance osteoblast differentiation in primary osteoblasts.\nThe bone anabolic effects of the compounds were shown\nusing ex vivo-cultured calvaria. Nuclear magnetic resonance (NMR)\ntitration analysis confirmed interaction between Dvl PDZ domain\nand KY-02061, a representative of the screened compounds. Oral\nadministration of KY-02327, one of 55 newly synthesized KY-02061\nanalogs, successfully rescued bone loss in the ovariectomized\n(OVX) mouse model. In conclusion, small-molecule inhibitors of the\nDvlââ?¬â??CXXC5 interaction that block negative feedback regulation of\nWnt/b-catenin signaling are potential candidates for the\ndevelopment of bone anabolic anti-osteoporosis drugs....
Hydro-alcoholic fruit extract of Cordia myxa was considerably effective on curing acute inflammation in mouse\nmodel. Previous studies suggested significant anti-inflammatory activities as well as potential anticancer agent of\n-amyrins in seeds. Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX) is significant in\ncancer prevention and therapeutics although this inhibition with chemo-drugs has its own side-effects. It is\nshown that these enzymes pathways are related to several cancers including colon, breast and lung cancer. This\nstudy was conducted based on Cordia species� -amyrins as a safer natural anti-cancer compound for inhibition\nof COX-2 and 5-LOX enzymes by molecular docking. The X-ray crystal structure of COX2 / 5-LOX enzymes\nand -amyrins was retrieved and energetically minimized respectively. The binding site and surface of enzymes\nwere detected. Docking studies were performed by AutoDock 4.2 using Lamarckian genetic algorithm (LGA).\nFinally drug likeness, molecular pharmacokinetic properties and toxicity of -amyrins was calculated. Molecular\nDocking revealed hydrogen and hydrophobic interactions between -amyrins with both active sites of COX-2\nand 5-LOX enzymes. Interestingly, it covalently bonded to Fe cofactor of 5-LOX enzyme and chelated this molecule.\nBase on binding energies (G) -amyrin has more inhibitory effects on 5-LOX (-10.45 Kcal/mol) than\nCOX-2 (-8.02 Kcal/mol). Analysis of molecular pharmacokinetic parameters suggested that -amyrins complied\nwith most sets of Lipinski's rules, and so it could be a suitable ligand for docking studies. Eventually, bioactivity\nscore showed -amyrins possess considerable biological activities as nuclear receptor, enzyme inhibitor, GPCR\nand protease inhibitor ligand. These results clearly demonstrate that -amyrins could act as potential highly selective\nCOX-/5-LOX inhibitor. Also, it is a safe compound in comparison with classical non-steroidal antiinflammatory\ndrugs (NSAIDs) that are known as cancer preventive agents, since it is free of side effects on human\nbody and it can be a promising drug for cancer therapeutics....
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