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https://www.readbyqxmd.com/read/28426652/cheminformatics-aided-discovery-of-small-molecule-protein-protein-interaction-ppi-dual-inhibitors-of-tumor-necrosis-factor-tnf-and-receptor-activator-of-nf-%C3%AE%C2%BAb-ligand-rankl
#1
Georgia Melagraki, Evangelos Ntougkos, Vagelis Rinotas, Christos Papaneophytou, Georgios Leonis, Thomas Mavromoustakos, George Kontopidis, Eleni Douni, Antreas Afantitis, George Kollias
We present an in silico drug discovery pipeline developed and applied for the identification and virtual screening of small-molecule Protein-Protein Interaction (PPI) compounds that act as dual inhibitors of TNF and RANKL through the trimerization interface. The cheminformatics part of the pipeline was developed by combining structure-based with ligand-based modeling using the largest available set of known TNF inhibitors in the literature (2481 small molecules). To facilitate virtual screening, the consensus predictive model was made freely available at: http://enalos...
April 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28426554/barking-up-the-right-tree-advancing-our-understanding-and-treatment-of-lymphoma-with-a-spontaneous-canine-model
#2
Dania Villarnovo, Angela L McCleary-Wheeler, Kristy L Richards
PURPOSE OF REVIEW: Spontaneous lymphoma in pet dogs is increasingly recognized as an ideal model for studying the disease in humans and for developing new targeted therapeutics for patients. Increasing interest by funding agencies, the private sector, and multidisciplinary academic collaborations between different disciplines and sectors now enables large knowledge gaps to be addressed and provides additional proof-of-concept examples to showcase the significance of the canine model. RECENT FINDINGS: The current review addresses the rationale for a canine lymphoma model including the valuable role it can play in drug development, serving as a link between mouse xenograft models and human clinical trials and the infrastructure that is now in place to facilitate these studies...
April 19, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28425478/data-intensive-genome-level-analysis-for-identifying-novel-non-toxic-drug-targets-for-multi-drug-resistant-mycobacterium-tuberculosis
#3
Divneet Kaur, Rintu Kutum, Debasis Dash, Samir K Brahmachari
We report the construction of a novel Systems Biology based virtual drug discovery model for the prediction of non-toxic metabolic targets in Mycobacterium tuberculosis (Mtb). This is based on a data-intensive genome level analysis and the principle of conservation of the evolutionarily important genes. In the 1623 sequenced Mtb strains, 890 metabolic genes identified through a systems approach in Mtb were evaluated for non-synonymous mutations. The 33 genes showed none or one variation in the entire 1623 strains, including 1084 Russian MDR strains...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28423764/an-automatic-approach-for-analyzing-treatment-effectiveness-based-on-medication-hierarchy-the-myocardial-infarction-case-study
#4
Yingxue Li, Yiying Hu, Jingang Yang, Xiang Li, Haifeng Liu, Guotong Xie, Meilin Xu, Jingyi Hu, Yuejin Yang
Treatment effectiveness plays a fundamental role in patient therapies. In most observational studies, researchers often design an analysis pipeline for a specific treatment based on the study cohort. To evaluate other treatments in the data set, much repeated and multifarious work including cohort construction, statistical analysis need to be done. In addition, as treatments are often with an intrinsic hierarchical relationship, many rational comparable treatment pairs can be derived as new treatment variables besides the original single treatment one from the original cohort data set...
2017: Studies in Health Technology and Informatics
https://www.readbyqxmd.com/read/28414209/polypharmacological-in-silico-bioactivity-profiling-and-experimental-validation-uncovers-sedative-hypnotic-effects-of-approved-and-experimental-drugs-in-rat
#5
Georgios Drakakis, Keith A Wafford, Suzanne C Brewerton, Michael J Bodkin, David A Evans, Andreas Bender
In this work, we describe the computational ('in silico') mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for each mode-of-action into account, and which was followed by successful prospective in vitro and in vivo validation. Using sleep-related phenotypic readouts describing both efficacy and side-effects for 491 compounds tested in rat, we defined an 'optimal' (desirable) sleeping pattern. Compounds were subjected to in silico target prediction (which was experimentally confirmed for 21 out of 28 cases, corresponding to 75%), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles...
April 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28412959/opportunities-for-developing-therapies-for-rare-genetic-diseases-focus-on-gain-of-function-and-allostery
#6
Binbin Chen, Russ B Altman
BACKGROUND: Advances in next generation sequencing technologies have revolutionized our ability to discover the causes of rare genetic diseases. However, developing treatments for these diseases remains challenging. In fact, when we systematically analyze the US FDA orphan drug list, we find that only 8% of rare diseases have an FDA-designated drug. Our approach leverages three primary insights: first, diseases with gain-of-function mutations and late onset are more likely to have drug options; second, drugs are more often inhibitors than activators; and third, some disease-causing proteins can be rescued by allosteric activators in diseases due to loss-of-function mutations...
April 17, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28405804/cytoprotective-drug-tissue-plasminogen-activator-protease-interaction-assays-screening-of-two-novel-cytoprotective-chromones
#7
Paul A Lapchak, Jacqueline M Lara, Paul D Boitano
Tissue plasminogen activator (tPA) is currently used in combination with endovascular procedures to enhance recanalization and cerebral reperfusion and is also currently administered as standard-of-care thrombolytic therapy to patients within 3-4.5 h of an ischemic stroke. Since tPA is not neuroprotective or cytoprotective, adjuvant therapy with a neuroprotective or an optimized cytoprotective compound is required to provide the best care to stroke victims to maximally promote clinical recovery. In this article, we describe the use of a sensitive standardized protease assay with CH3SO2-D-hexahydrotyrosine-Gly-Arg-p-nitroanilide•AcOH, a chromogenic protease substrate that is cleaved to 4-nitroaniline (p-nitroaniline) and measured spectrophotometrically at 405 nm (OD405 nm), and how the assay can be used as an effective screening assay to study drug-tPA interactions...
April 12, 2017: Translational Stroke Research
https://www.readbyqxmd.com/read/28403774/pharmacogenetics-of-aromatase-inhibitors-in-endocrine-responsive-breast-cancer-lessons-learnt-from-tamoxifen-and-cyp2d6-genotyping
#8
Karin Jeanne Baatjes, Magda Conradie, Justus Paul Apffelstaedt, Maritha Kotze
BACKGROUND: Genetics play a significant role in drug metabolism of endocrine therapy of breast cancer. These aspects have been studied extensively in patients on tamoxifen, but the pharmacogenetics of aromatase inhibitors are less established. In contrast to the protective effect of tamoxifen, aromatase inhibitors are linked with an increased risk for bone loss and fractures. OBJECTIVE: This review outlines key issues around implementation of pharmacogenetics of cytochrome P450 and tamoxifen as a model for optimal use of aromatase inhibitors in postmenopausal women with estrogen receptor positive breast cancer...
April 12, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28402142/development-of-separation-technology-for-the-removal-of-radium-223-from-targeted-thorium-conjugate-formulations-part-ii-purification-of-targeted-thorium-conjugates-on-cation-exchange-columns
#9
Janne Olsen Frenvik, Knut Dyrstad, Solveig Kristensen, Olav B Ryan
Tumour targeting pharmaceuticals will play a crucial role in future pharma pipelines. The Targeted Thorium Conjugate (TTC) therapeutic platform could provide real benefit to patients, whereby targeting moieties like monoclonal antibodies are radiolabelled with the alpha-emitting radionuclide thorium-227 ((227)Th, t1/2=18.7 days). A potential problem could be the accumulation of the long-lived daughter nuclide radium-223 ((223)Ra, t1/2=11.4 days) in the drug product during manufacture and distribution. Therefore, the level of (223)Ra must be standardised before administration to the patient...
April 12, 2017: Drug Development and Industrial Pharmacy
https://www.readbyqxmd.com/read/28391063/drugclust-a-machine-learning-approach-for-drugs-side-effects-prediction
#10
Giovanna Maria Dimitri, Pietro Lió
BACKGROUND: Identification of underlying mechanisms behind drugs side effects is of extreme interest and importance in drugs discovery today. Therefore machine learning methodology, linking such different multi features aspects and able to make predictions, are crucial for understanding side effects. METHODS: In this paper we present DrugClust, a machine learning algorithm for drugs side effects prediction. DrugClust pipeline works as follows: first drugs are clustered with respect to their features and then side effects predictions are made, according to Bayesian scores...
March 30, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28387389/the-year-s-new-drugs-biologics-2016-part-ii-trends-and-highlights-of-an-unforgettable-year
#11
A I Graul, C Dulsat, M Tracy, E Cruces
This eagle's-eye overview of the drug industry in 2016 provides insight into some of last year's top stories, including disease outbreaks that drove R&D, orphan drug development, pipeline attrition, drug pricing, and the ongoing movement in M&A. We also consider recent political events in the U.S. and U.K. and their potential impact on the industry in the years to come, and take a glimpse into the crystal ball to anticipate the new drugs that may be approved in 2017.
February 2017: Drugs of Today
https://www.readbyqxmd.com/read/28386634/insights-and-lessons-from-a-scientific-conference-on-non-invasive-delivery-of-macromolecules
#12
Ronak Savla, Randall J Mrsny, Kinam Park, Isabelle Aubert, Cornell Stamoran
A growing share of the pharmaceutical development pipeline is occupied by macromolecule drugs, which are primarily administered by injection. Despite decades of attempts, non-invasive delivery of macromolecules has seen only a few success stories. Potential benefits of non-invasive administration include better patient acceptance and adherence and potentially better efficacy and safety. Greater inter-disciplinary dialogue and collaboration are integral to realizing these benefits.
April 6, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28385536/mining-the-topography-and-dynamics-of-the-4d-nucleome-to-identify-novel-cns-drug-pathways
#13
Gerald A Higgins, Ari Allyn-Feuer, Patrick Georgoff, Vahagn Nikolian, Hasan Alam, Brian D Athey
The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications...
April 3, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28384139/antifungal-drug-testing-by-combining-minimal-inhibitory-concentration-testing-with-target-identification-by-gas-chromatography-mass-spectrometry
#14
Christoph Müller, Ulrike Binder, Franz Bracher, Martin Giera
Fungal infections and their increasing resistance to antibiotics are an emerging threat to public health. Novel antifungal drugs, as well technologies that can help us bolster the antimicrobial pipeline and understand resistance mechanisms, are needed. The ergosterol biosynthetic pathway is one potential target for antifungal drugs. Here we describe how antifungal susceptibility testing can be combined with target identification in distal ergosterol biosynthesis by means of gas chromatography-mass spectrometry...
May 2017: Nature Protocols
https://www.readbyqxmd.com/read/28382867/an-integrated-computational-approach-for-plant-based-protein-tyrosine-phosphatase-non-receptor-type-1-inhibitors
#15
Shabana Bibi, Katsumi Sakata
BACKGROUND: Protein tyrosine phosphatase non-receptor type 1 is a therapeutic target for the type 2 diabetes mellitus. According to the International Diabetes Federation 2015 report, one out of 11 adults suffer from diabetes mellitus globally. OBJECTIVE: Current anti-diabetic drugs can cause life-threatening side-effects. The present study proposes a pipeline for the development of effective and plant-derived anti-diabetic drugs that may be safer and better tolerated...
April 6, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28381603/comprehensive-whole-genome-sequencing-and-reporting-of-drug-resistance-profiles-on-clinical-cases-of-mycobacterium-tuberculosis-in-new-york-state
#16
Joseph Shea, Tanya A Halse, Pascal Lapierre, Matthew Shudt, Donna Kohlerschmidt, Patrick Van Roey, Ronald Limberger, Jill Taylor, Vincent Escuyer, Kimberlee A Musser
Whole-genome sequencing (WGS) is a newer alternative for tuberculosis (TB) diagnostics, capable of providing rapid drug resistance profiles while performing species identification and capturing the data necessary for genotyping. Our laboratory developed and validated a comprehensive and sensitive WGS assay to characterize Mycobacterium tuberculosis and other M. tuberculosis complex (MTBC) strains, comprised of a novel DNA extraction, optimized library preparation, paired-end WGS, and an in-house developed bioinformatics pipeline...
April 5, 2017: Journal of Clinical Microbiology
https://www.readbyqxmd.com/read/28379727/accelerating-precision-drug-development-and-drug-repurposing-by-leveraging-human-genetics
#17
Jill M Pulley, Jana K Shirey-Rice, Robert R Lavieri, Rebecca N Jerome, Nicole M Zaleski, David M Aronoff, Lisa Bastarache, Xinnan Niu, Kenneth J Holroyd, Dan M Roden, Eric P Skaar, Colleen M Niswender, Lawrence J Marnett, Craig W Lindsley, Leeland B Ekstrom, Alan R Bentley, Gordon R Bernard, Charles C Hong, Joshua C Denny
The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains...
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28377116/pharmacological-screening-technologies-for-venom-peptide-discovery
#18
REVIEW
Jutty Rajan Prashanth, Nojod Hasaballah, Irina Vetter
Venomous animals occupy one of the most successful evolutionary niches and occur on nearly every continent. They deliver venoms via biting and stinging apparatuses with the aim to rapidly incapacitate prey and deter predators. This has led to the evolution of venom components that act at a number of biological targets - including ion channels, G-protein coupled receptors, transporters and enzymes - with exquisite selectivity and potency, making venom-derived components attractive pharmacological tool compounds and drug leads...
April 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28369768/pharma-perspective-on-drug-repurposing
#19
REVIEW
Y Cha, T Erez, I J Reynolds, D Kumar, J Ross, G Koytiger, R Kusko, B Zeskind, S Risso, E Kagan, S Papapetropoulos, I Grossman, D Laifenfeld
Drug repurposing holds the potential to bring medications with known safety profiles to new patient populations. Numerous examples exist for the identification of new indications for existing molecules, most stemming from serendipitous findings or focused recent efforts specifically limited to the mode of action of a specific drug. In recent years, the need for new approaches to drug R&D, combined with the advent of big-data repositories and associated analytics has generated interest in developing systematic approaches to drug repurposing...
March 29, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28366666/a-high-content-microscopy-assay-to-determine-drug-activity-against-intracellular-mycobacterium-tuberculosis
#20
Alyssa J Manning, Yulia Ovechkina, Amanda McGillivray, Lindsay Flint, David M Roberts, Tanya Parish
Tuberculosis is one of the infectious diseases with the greatest global burden, affecting millions of people. The rise of multi- and extensively-drug resistant forms of Mycobacterium tuberculosis over the last few decades has highlighted the urgent need for development of new drugs to treat the disease. Many drug development pipelines are based on in vitro assays examining a compound's effect on M. tuberculosis alone. These do not account for the effect of a compound on mammalian cells nor the interaction between host and pathogen...
March 31, 2017: Methods: a Companion to Methods in Enzymology
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