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https://www.readbyqxmd.com/read/29045053/ensamble-based-adme-tox-profiling-and-virtual-screening-for-the-discovery-of-new-inhibitors-of-the-leishmania-mexicana-cysteine-protease-cpb2-8%C3%AE-cte
#1
Angela Scala, Antonio Rescifina, Nicola Micale, Anna Piperno, Tanja Schirmeister, Louis Maes, Giovanni Grassi
In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8ΔCTE, fused benzo[b]thiophenes and β,β'-triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate to excellent activity (12-90% inhibition of the target enzyme at 20 μM). The most promising compounds were selected for further profiling including in vitro cell-based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non-covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3'-triketones with a Y-topology...
October 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29039210/mailbox-tox-ingestion-of-a-pharmaceutical-product-stolen-from-a-mailbox
#2
Jacob A Kanter, Neeraj Chhabra, Michele Zell-Kanter
No abstract text is available yet for this article.
October 1, 2017: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/28990518/click-reactions-in-chemistry-of-triterpenes-advances-towards-development-of-potential-therapeutics
#3
Jan Pokorný, Lucie Borková, Milan Urban
Triterpenoids are natural compounds with a large variety of biological activities such as anticancer, antiviral, antibacterial, antifungal, antiparazitic, antiinflammatory and others. Despite their low toxicity and simple availability from the natural resources, their clinical use is still severely limited by their higher IC50 and worse pharmacological properties than in the currently used therapeutics. This fact encouraged a number of researchers to develop new terpenic derivatives more suitable for the potential clinical use...
October 9, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28988506/in-silico-adme-tox-modeling-progress-and-prospects
#4
Saeed Alqahtani
Although significant progress has been made in high-throughput screening of absorption, distribution, metabolism and excretion, and toxicity (ADME-Tox) properties in drug discovery and development, in silico ADME-Tox prediction continues to play an important role in facilitating the appropriate selection of candidate drugs by pharmaceutical companies prior to expensive clinical trials. Areas covered: This review provides an overview of the available in silico models that have been used to predict the ADME-Tox properties of compounds...
October 9, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28985315/cross-reactivity-of-pantoprazole-with-three-commercial-cannabinoids-immunoassays-in-urine
#5
Isabel Gomila, Bernardino Barceló, Antonio Rosell, Sonia Avella, Laura Sahuquillo, Macarena Dastis
Pantoprazole is a frequently prescribed proton pump inhibitor (PPI) commonly utilized in the management of gastrointestinal symptoms. Few substances have proved to cause a false-positive cannabinoid urine screen. However, a case of false-positive urine cannabinoid screen in a patient who received a pantoprazole dose has been recently published. The purpose of this study was to determine the potential cross-reactivity of pantoprazole in the cannabinoid immunoassays: Alere Triage® TOX Drug Screen, KIMS® Cannabinoids II and DRI® Cannabinoids Assay...
July 13, 2017: Journal of Analytical Toxicology
https://www.readbyqxmd.com/read/28974511/tox-regulates-growth-dna-repair-and-genomic-instability-in-t-cell-acute-lymphoblastic-leukemia
#6
Riadh Lobbardi, Jordan Pinder, Barbara Martinez-Pastor, Marina Theodorou, Jessica S Blackburn, Brian J Abraham, Yuka Namiki, Marc Mansour, Nouran S Abdelfattah, Aleksey Molodtsov, Gabriela Alexe, Debra Toiber, Manon de Waard, Esha Jain, Myriam Boukhali, Mattia Lion, Deepak Bhere, Khalid Shah, Alejandro Gutierrez, Kimberly Stegmaier, Lewis B Silverman, Ruslan I Sadreyev, John M Asara, Marjorie A Oettinger, Wilhelm Haas, A Thomas Look, Richard A Young, Raul Mostoslavsky, Graham Dellaire, David M Langenau
T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection-associated high mobility box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit Non-Homologous End Joining repair (NHEJ)...
October 3, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28966486/use-of-culture-and-elisa-based-toxin-assay-for-detecting-clostridium-difficile-a-neglected-pathogen-a-single-center-study-from-a-tertiary-care-setting
#7
Sujata Lall, Gita Nataraj, Preeti Mehta
INTRODUCTION: Clostridium difficile is a Gram-positive spore-bearing anaerobic bacillus increasingly associated with both community- and hospital-acquired colitis and diarrhea. It is the most common identifiable bacterial cause of healthcare-associated diarrhea associated with antibiotic use and one of the most common anaerobic infections. The diagnosis of C. difficile infection includes detection of toxin A/B in stool specimens by direct enzyme immunoassay, culture of pathogen from the stool specimens using a selective agar Cycloserine-Cefoxitin fructose agar (CCFA), tissue culture assay, and detection of glutamate dehydrogenase an enzyme produced by C...
October 2017: Journal of Laboratory Physicians
https://www.readbyqxmd.com/read/28961788/faf-drugs4-free-adme-tox-filtering-computations-for-chemical-biology-and-early-stages-drug-discovery
#8
David Lagorce, Lina Bouslama, Jerome Becot, Maria A Miteva, Bruno O Villoutreix
Motivation: Identification of small molecules that could be interesting starting points for drug discovery or to investigate a biological system as in chemical biology endeavors is both time consuming and costly. In silico approaches that assist the design of quality compound collections or help to prioritize molecules before synthesis or purchase are therefore valuable. Here quality refers to the selection of molecules that pass one or several selected filters that can be tuned by the users according to the project and the stage of the project...
July 29, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28943953/six-low-penetrance-snps-for-the-estimation-of-breast-cancer-heritability-a-family-based-study-in-caucasian-italian-patients
#9
Simona De Summa, Francesca Graziano, Brunella Pilato, Rosamaria Pinto, Katia Danza, Rosanna Lacalamita, Simona Serratì, Domenico Sambiasi, Mario Grassi, Stefania Tommasi
Breast cancer is a malignancy with a strong heritable component. Genetic counseling has been principally focused on families carrying high-penetrance breast cancer 1/2, early onset genes. Current modeling suggests that the majority of the unexplained fraction of familial risk is likely to be explained by a polygenic model. The aim of the present study was to estimate the heritability (h(2)) of breast cancer susceptibility through the analysis of 6 single nucleotide polymorphisms (SNPs), nuclear mitotic apparatus protein 1, cyclin D1, cytochrome C oxidase copper chaperone, fibroblast growth factor receptor 2, TOX high mobility group box family member 3 and solute carrier family 4 member 7...
October 2017: Oncology Letters
https://www.readbyqxmd.com/read/28941159/molecular-modeling-studies-of-pseudouridine-isoxazolidinyl-nucleoside-analogues-as-potential-inhibitors-of-the-pseudouridine-5-monophosphate-glycosidase
#10
Giuseppe Floresta, Venerando Pistarà, Emanuele Amata, Maria Dichiara, Arcangelo Damigella, Agostino Marrazzo, Orazio Prezzavento, Francesco Punzo, Antonio Rescifina
In this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5'-monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME-Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5'-monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N-protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5'-monophosphate glycosidase, leading to the enzyme inhibition...
September 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28940036/toxicarioside-n-induces-apoptosis-in-human-gastric-cancer-sgc-7901-cell-by-activating-the-p38mapk-pathway
#11
Huan-Ge Zhao, Song-Lin Zhou, Ying-Ying Lin, Hao-Fu Dai, Feng-Ying Huang
Natural plant compounds with potent proliferation inhibition and apoptosis induction properties have been screened as novel anticancer drugs. Toxicarioside N (Tox N) was isolated from the seeds of the tropical plant Antiaris toxicaria in Hainan province, China. To our knowledge, the effects that Tox N has on the apoptosis of SGC-7901 cells and its potential mechanism have never been investigated. In this study, we detected the anticancer activities of Tox N and explored the potential mechanism in the human gastrointestinal cancer cell line SGC-7901...
September 22, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28939559/microbiome-symbionts-and-diet-diversity-incur-costs-on-the-immune-system-of-insect-larvae
#12
Indrikis A Krams, Sanita Kecko, Priit Jõers, Giedrius Trakimas, Didzis Elferts, Ronalds Krams, Severi Luoto, Markus J Rantala, Inna Inashkina, Dita Gudrā, Dāvids Fridmanis, Jorge Contreras-Garduño, Lelde Grantiņa-Ieviņa, Tatjana Krama
Communities of symbiotic microorganisms that colonize the gastrointestinal tract play an important role in food digestion and protection against opportunistic microbes. Diet diversity increases the number of symbionts in the intestines, a benefit that is considered to impose no cost for the host organism. However, less is known about the possible immunological investments that hosts have to make in order to control the infections caused by symbiont populations that increase due to diet diversity. By using taxonomical composition analysis of the 16S rRNA V3 region, we show that Enterococci are the dominating group of bacteria in the midgut of the larvae of the greater wax moth (Galleria mellonella)...
September 22, 2017: Journal of Experimental Biology
https://www.readbyqxmd.com/read/28935887/bitter-or-not-bitterpredict-a-tool-for-predicting-taste-from-chemical-structure
#13
Ayana Dagan-Wiener, Ido Nissim, Natalie Ben Abu, Gigliola Borgonovo, Angela Bassoli, Masha Y Niv
Bitter taste is an innately aversive taste modality that is considered to protect animals from consuming toxic compounds. Yet, bitterness is not always noxious and some bitter compounds have beneficial effects on health. Hundreds of bitter compounds were reported (and are accessible via the BitterDB http://bitterdb.agri.huji.ac.il/dbbitter.php ), but numerous additional bitter molecules are still unknown. The dramatic chemical diversity of bitterants makes bitterness prediction a difficult task. Here we present a machine learning classifier, BitterPredict, which predicts whether a compound is bitter or not, based on its chemical structure...
September 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28874590/discovery-of-peptide-ligands-through-docking-and-virtual-screening-at-nicotinic-acetylcholine-receptor-homology-models
#14
Abba E Leffler, Alexander Kuryatov, Henry A Zebroski, Susan R Powell, Petr Filipenko, Adel K Hussein, Juliette Gorson, Anna Heizmann, Sergey Lyskov, Richard W Tsien, Sébastien F Poget, Annette Nicke, Jon Lindstrom, Bernardo Rudy, Richard Bonneau, Mandë Holford
Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the α4β2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin α-GID that antagonizes it...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28842948/leveraging-a-cho-cell-line-toolkit-to-accelerate-biotherapeutics-into-the-clinic
#15
Chapman Wright, Christina Alves, Scott Estes, John Pieracci, Rashmi Kshirsagar
The Biogen upstream platform is capable of delivering equivalent quality material throughout the cell line generation process. This allows us to rapidly deliver high quality biopharmaceuticals to patients with unmet medical needs. The drive to reduce time-to-market led the cell engineering group to develop an expression system that can enable this strategy. We have developed a clonal CHO host cell line that can routinely produce consistent antibody material at high titers throughout the cell line generation process...
August 26, 2017: Biotechnology Progress
https://www.readbyqxmd.com/read/28840991/evaluation-of-the-triage-tox-drug-screen-assay-for-detection-of-11-drugs-of-abuse-and-therapeutic-drugs
#16
Hae In Bang, Mi Ae Jang, Yong Wha Lee
The demand for rapid and broad clinical toxicology screens is on the rise. Recently, a new rapid toxicology screening test, the Triage TOX Drug Screen (Alere Inc., USA), which can simultaneously detect 11 drugs of abuse and therapeutic drugs with an instrument-read cartridge, was developed. In the present study, we evaluated the efficacy of this new on-site immunoassay using 105 urine specimens; the results were compared with those obtained by using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-TMS)...
November 2017: Annals of Laboratory Medicine
https://www.readbyqxmd.com/read/28837407/a-dynamic-energy-based-model-to-analyze-sublethal-effects-of-chronic-gamma-irradiation-in-the-nematode-caenorhabditis-elegans
#17
Catherine Lecomte-Pradines, Turid Hertel-Aas, Claire Coutris, Rodolphe Gilbin, Deborah Oughton, Frédéric Alonzo
Understanding how toxic contaminants affect wildlife species at various levels of biological organization (subcellular, histological, physiological, organism, and population levels) is a major research goal in both ecotoxicology and radioecology. A mechanistic understanding of the links between different observed perturbations is necessary to predict the consequences for survival, growth, and reproduction, which are critical for population dynamics. In this context, experimental and modeling studies were conducted using the nematode Caenorhabditis elegans...
2017: Journal of Toxicology and Environmental Health. Part A
https://www.readbyqxmd.com/read/28829594/cd22-ligands-on-a-natural-n-glycan-scaffold-efficiently-deliver-toxins-to-b-lymphoma-cells
#18
Wenjie Peng, James C Paulson
CD22 is a sialic acid-binding immunoglobulin-like lectin (Siglec) that is highly expressed on B-cells and B cell lymphomas, and is a validated target for antibody and nanoparticle based therapeutics. However, cell targeted therapeutics are limited by their complexity, heterogeneity, and difficulties in production. We describe here a chemically defined natural N-linked glycan scaffold that displays high affinity CD22 glycan ligands and outcompetes the natural ligand for the receptor, resulting in single molecule binding to CD22 and endocytosis into cells...
August 31, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28816188/assessment-of-changes-in-nickel-and-chromium-levels-in-the-gingival-crevicular-fluid-during-fixed-orthodontic-treatment
#19
Vinny Bhasin, Swati J Pustake, Viprat Joshi, Anil Tiwari, Meenakshi Bhasin, Ramandeep S Punia
BACKGROUND: Various components of appliances used in fixed orthodontic treatment are fabricated from materials that are highly resistant in nature and have high strength and biocompatibility. Corrosion of materials occurs inside the oral cavity due to numerous environmental or oral factors that act on them. These factors include temperature, pH variation, salivary conditions, mechanical loads, microbiological and enzymatic activity, and various food components. Gingival crevicular fluid (GCF) is the material obtained from the gingival sulcus and might act as a potential source for various biomarkers in the orthodontic setup because inflammatory-induced response is directly related to orthodontic forces in GCF...
August 1, 2017: Journal of Contemporary Dental Practice
https://www.readbyqxmd.com/read/28780479/q-twist-analysis-of-patients-with-metastatic-castrate-naive-prostate-cancer-treated-by-androgen-deprivation-therapy-with-or-without-docetaxel-in-the-randomised-phase-iii-getug-afu-15-trial
#20
RANDOMIZED CONTROLLED TRIAL
P Marino, P Sfumato, F Joly, K Fizazi, S Oudard, S Culine, M Habibian, J-M Boher, G Gravis
BACKGROUND: Early chemotherapy has recently become a new standard of care for patients with metastatic castrate-naive prostate cancer (mCNPC). The survival benefit is evident in patients with high-volume disease, but less clear in those with low-volume disease. Here, we assessed the trade-offs between toxicity and survival using a Quality-adjusted Time Without Symptoms of disease and Toxicity of treatment (Q-TWiST) analysis. PATIENTS AND METHODS: This analysis was performed from the data of the Genito-Urinary Oncology Group (GETUG)-AFU 15 phase III trial evaluating the benefits of docetaxel (D) combined with androgen deprivation therapy (ADT) versus ADT alone in 385 mCNPC patients...
October 2017: European Journal of Cancer
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