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https://www.readbyqxmd.com/read/28544857/new-treatment-directions-for-ipf-current-status-of-ongoing-and-upcoming-clinical-trials
#1
Francesco Macagno, Francesco Varone, Paolo Maria Leone, Pier-Valerio Mari, Loredana Panico, Ludovica Berardini, Luca Richeldi
The main objective of this review is to explore the wide and expanding field of new clinical trials in IPF. Recent trials have confirmed the efficacy of the approved drugs pirfenidone and nintedanib; nonetheless, the discovery of new biological pathways has opened new horizons in this field. Areas Covered: New strategies against matrix deposition are under study and so is for the role of immunity and autoimmunity. Recent advances in the use of stem cells are opening new possibilities for the recovery of damaged lung tissues...
May 25, 2017: Expert Review of Respiratory Medicine
https://www.readbyqxmd.com/read/28544567/chemoproteomics-aided-medicinal-chemistry-for-the-discovery-of-epha2-inhibitors
#2
Stephanie Heinzlmeir, Jonas Lohse, Tobias Treiber, Denis Kudlinzki, Verena Linhard, Santosh Lakshmi Gande, Sridhar Sreeramulu, Krishna Saxena, Xiaofeng Liu, Mathias Wilhelm, Harald Schwalbe, Bernhard Kuster, Guillaume Médard
The receptor tyrosine kinase EPHA2 has gained interest as therapeutic drug target in cancer and infectious diseases. However, EPHA2 research and EPHA2-based therapies have been hampered by the lack of selective small molecule inhibitors. Here, we report on the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor Dasatinib as a lead structure. We designed hybrid structures of Dasatinib and the previously known EPHA2 binders CHEMBL249097, PD-173955 and a known EPHB4 inhibitor in order to exploit both the ATP pocket entrance as well as the ribose pocket as binding epitopes in the kinase EPHA2...
May 24, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28544415/inertial-microfluidic-cell-stretcher-imcs-fully-automated-high-throughput-and-near-real-time-cell-mechanotyping
#3
Yanxiang Deng, Steven P Davis, Fan Yang, Kevin S Paulsen, Maneesh Kumar, Rebecca Sinnott DeVaux, Xianhui Wang, Douglas S Conklin, Assad Oberai, Jason I Herschkowitz, Aram J Chung
Mechanical biomarkers associated with cytoskeletal structures have been reported as powerful label-free cell state identifiers. In order to measure cell mechanical properties, traditional biophysical (e.g., atomic force microscopy, micropipette aspiration, optical stretchers) and microfluidic approaches were mainly employed; however, they critically suffer from low-throughput, low-sensitivity, and/or time-consuming and labor-intensive processes, not allowing techniques to be practically used for cell biology research applications...
May 23, 2017: Small
https://www.readbyqxmd.com/read/28544378/concise-review-induced-pluripotent-stem-cell-based-drug-discovery-for-mitochondrial-disease
#4
REVIEW
Gizem Inak, Carmen Lorenz, Pawel Lisowski, Annika Zink, Barbara Mlody, Alessandro Prigione
High attrition rates and loss of capital plague the drug discovery process. This is particularly evident for mitochondrial disease that typically involves neurological manifestations and is caused by nuclear or mitochondrial DNA defects. This group of heterogeneous disorders is difficult to target because of the variability of the symptoms among individual patients and the lack of viable modeling systems. The use of induced pluripotent stem cells (iPSCs) might significantly improve the search for effective therapies for mitochondrial disease...
May 22, 2017: Stem Cells
https://www.readbyqxmd.com/read/28544095/phenotypic-assays-for-mycobacterium-tuberculosis-infection
#5
Ok-Ryul Song, Nathalie Deboosere, Vincent Delorme, Christophe J Queval, Gaspard Deloison, Elisabeth Werkmeister, Frank Lafont, Alain Baulard, Raffaella Iantomasi, Priscille Brodin
Tuberculosis (TB) is still a major global threat, killing more than one million persons each year. With the constant increase of Mycobacterium tuberculosis strains resistant to first- and second-line drugs, there is an urgent need for the development of new drugs to control the propagation of TB. Although screenings of small molecules on axenic M. tuberculosis cultures were successful for the identification of novel putative anti-TB drugs, new drugs in the development pipeline remains scarce. Host-directed therapy may represent an alternative for drug development against TB...
May 19, 2017: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
https://www.readbyqxmd.com/read/28543443/structural-review-of-ppar%C3%AE-in-complex-with-ligands-cartesian-and-dihedral-angle-principal-component-analyses-of-x-ray-crystallographic-data
#6
Åsmund Kaupang, Tuomo Laitinen, Antti Poso, Trond Vidar Hansen
Two decades of research into the ligand-dependent modulation of the activity of the peroxisome proliferator-activated receptor γ (PPARγ) have demonstrated the heterogeneous modes of action of PPARγ ligands, in terms of their interaction surfaces in the ligand-binding pocket, binding stoichiometry and ability to interact with functionally important parts of the receptor, through both direct and allosteric mechanisms. These findings signal the complex mechanistic bases of the distinct biological effects of different classes of PPARγ ligands...
May 24, 2017: Proteins
https://www.readbyqxmd.com/read/28542953/zebrafish-tmem230a-cooperates-with-the-delta-notch-signaling-pathway-to-modulate-endothelial-cell-number-in-angiogenic-vessels
#7
Silvia Carra, Lorenzo Sangiorgio, Paride Pelucchi, Solei Cermenati, Alessandra Mezzelani, Valentina Martino, Mira Palizban, Alberto Albertini, Martin Götte, James Kehler, Gianluca Deflorian, Monica Beltrame, Antonio Giordano, Rolland Reinbold, Franco Cotelli, Gianfranco Bellipanni, Ileana Zucchi
During embryonic development, new arteries and veins form from preexisting vessels in response to specific angiogenic signals. Angiogenic signaling is complex since not all endothelial cells exposed to angiogenic signals respond equally. Some cells will be selected to become tip cells and acquire migration and proliferation capacity necessary for vessel growth while others, the stalk cells become trailer cells that stay connected with pre-existing vessels and act as a linkage to new forming vessels. Additionally, stalk and tip cells have the capacity to interchange their roles...
May 25, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28542505/alzhcpi-a-knowledge-base-for-predicting-chemical-protein-interactions-towards-alzheimer-s-disease
#8
Jiansong Fang, Ling Wang, Yecheng Li, Wenwen Lian, Xiaocong Pang, Hong Wang, Dongsheng Yuan, Qi Wang, Ai-Lin Liu, Guan-Hua Du
Alzheimer's disease (AD) is a complicated progressive neurodegeneration disorder. To confront AD, scientists are searching for multi-target-directed ligands (MTDLs) to delay disease progression. The in silico prediction of chemical-protein interactions (CPI) can accelerate target identification and drug discovery. Previously, we developed 100 binary classifiers to predict the CPI for 25 key targets against AD using the multi-target quantitative structure-activity relationship (mt-QSAR) method. In this investigation, we aimed to apply the mt-QSAR method to enlarge the model library to predict CPI towards AD...
2017: PloS One
https://www.readbyqxmd.com/read/28542306/gene-signature-associated-with-benign-neurofibroma-transformation-to-malignant-peripheral-nerve-sheath-tumors
#9
Marta Martínez, Carlos O S Sorzano, Alberto Pascual-Montano, Jose M Carazo
Benign neurofibromas, the main phenotypic manifestations of the rare neurological disorder neurofibromatosis type 1, degenerate to malignant tumors associated to poor prognosis in about 10% of patients. Despite efforts in the field of (epi)genomics, the lack of prognostic biomarkers with which to predict disease evolution frustrates the adoption of appropriate early therapeutic measures. To identify potential biomarkers of malignant neurofibroma transformation, we integrated four human experimental studies and one for mouse, using a gene score-based meta-analysis method, from which we obtained a score-ranked signature of 579 genes...
2017: PloS One
https://www.readbyqxmd.com/read/28542202/unravelling-the-rate-of-action-of-hits-in-the-leishmania-donovani-box-using-standard-drugs-amphotericin-b-and-miltefosine
#10
Diana Tegazzini, Juan Cantizani, Imanol Peña, Julio Martín, Jose M Coterón
In recent years, the neglected diseases drug discovery community has elected phenotypic screening as the key approach for the identification of novel hit compounds. However, when this approach is applied, important questions related to the mode of action for these compounds remain unanswered. One of such questions is related to the rate of action, a useful piece of information when facing the challenge of prioritising the most promising hit compounds. In the present work, compounds of the "Leishmania donovani box" were evaluated using a rate of action assay adapted from a replicative intracellular high content assay recently developed...
May 25, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28541811/future-drug-discovery-in-renin-angiotensin-aldosterone-system-intervention
#11
Maria Tamargo, Juan Tamargo
Renin-angiotensin- aldosterone system inhibitors (RAASIs), including angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor blockers and mineralocorticoid receptor antagonists (MRAs), are the cornerstone for the treatment of cardiovascular and renal diseases. Areas covered: The authors searched MEDLINE, PubMed and ClinicalTrials.gov to identify eligible full-text English language papers. Herein, the authors discuss AT2-receptor agonists and ACE2/angiotensin-(1- 7)/Mas-receptor axis modulators, direct renin inhibitors, brain aminopeptidase A inhibitors, biased AT1R blockers, chymase inhibitors, multitargeted drugs, vaccines and aldosterone receptor antagonists as well as aldosterone synthase inhibitors...
May 25, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28541716/investigational-bet-bromodomain-protein-inhibitors-in-early-stage-clinical-trials-for-acute-myelogenous-leukemia-aml
#12
Thorsten Braun, Claude Gardin
Acute myelogenous leukemia (AML) is a heterogeneous group of malignancies driven by genetic mutations and deregulated epigenetic control. Relapse/refractory disease remains frequent in younger patients and even more so in older patients, including treatment with epigenetic drugs in this age group, mainly with hypomethylating agents. New treatment strategies are urgently needed. The recent discovery that epigenetic readers of the bromodomain (BRD) and extraterminal (BET) protein family, are crucial for AML maintenance by transcription of oncogenic c-MYC lead to rapid development of BET inhibitors entering clinical trials...
May 25, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28541680/regulatory-mechanisms-and-novel-therapeutic-targeting-strategies-for-protein-tyrosine-phosphatases
#13
Zhi-Hong Yu, Zhong-Yin Zhang
An appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and maintain cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic intervention. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent to an erroneous assumption that they are largely constitutive and housekeeping enzymes...
May 25, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28541665/identification-of-small-molecule-translesion-synthesis-inhibitors-that-target-the-rev1-ct-rir-protein-protein-interaction
#14
Vibhavari Sail, Alessandro A Rizzo, Nimrat Chatterjee, Radha Charan Dash, Zuleyha Ozen, Graham C Walker, Dmitry M Korzhnev, M Kyle Hadden
Translesion synthesis (TLS) is an important mechanism through which proliferating cells tolerate DNA damage during replication. The mutagenic Rev1/Polζ-dependent branch of TLS helps cancer cells survive first-line genotoxic chemotherapy and introduces mutations that can contribute to the acquired resistance so often observed with standard anti-cancer regimens. As such, inhibition of Rev1/Polζ-dependent TLS has recently emerged as a strategy to enhance the efficacy of first-line chemotherapy and reduce the acquisition of chemoresistance by decreasing tumor mutation rate...
May 25, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28541119/treatment-of-opioid-use-disorder-with-ibogaine-detoxification-and-drug-use-outcomes
#15
Thomas Kingsley Brown, Kenneth Alper
BACKGROUND: Ibogaine is a monoterpene indole alkaloid used in medical and nonmedical settings for the treatment of opioid use disorder. Its mechanism of action is apparently novel. There are no published prospective studies of drug use outcomes with ibogaine. OBJECTIVES: To study outcomes following opioid detoxification with ibogaine. METHODS: In this observational study, 30 subjects with DSM-IV Opioid Dependence (25 males, 5 females) received a mean total dose of 1,540 ± 920 mg ibogaine HCl...
May 25, 2017: American Journal of Drug and Alcohol Abuse
https://www.readbyqxmd.com/read/28540352/dataset-on-galanin-receptor-3-mutants-that-improve-recombinant-receptor-expression-and-stability-in-an-agonist-and-antagonist-bound-form
#16
Thao T Ho, Jasmine T Nguyen, Juping Liu, Pawel Stanczak, Aaron A Thompson, Yingzhuo G Yan, Jasmine Chen, Charles K Allerston, Charles L Dillard, Hao Xu, Nicholas J Shoger, Jill S Cameron, Mark E Massari, Kathleen Aertgeerts
Galanin Receptor 3 (GALR3) is a G-protein-coupled receptor with a widespread distribution in the brain and plays a role in a variety of physiologic processes including cognition/memory, sensory/pain processing, hormone secretion, and feeding behavior. Therefore, GALR3 is considered an attractive CNS drug target (Freimann et al., 2015) [1]. This dataset contains GALR3 point mutants that improve recombinant protein expression and thermal stability of the receptor contained in virus-like particles (VLPs) or obtained by detergent-purification of baculovirus-infected insect cells...
June 2017: Data in Brief
https://www.readbyqxmd.com/read/28539894/modulation-of-brain-activity-with-noninvasive-transcranial-direct-current-stimulation-tdcs-clinical-applications-and-safety-concerns
#17
REVIEW
Haichao Zhao, Lei Qiao, Dongqiong Fan, Shuyue Zhang, Ofir Turel, Yonghui Li, Jun Li, Gui Xue, Antao Chen, Qinghua He
Transcranial direct current stimulation (tDCS) is a widely-used tool to induce neuroplasticity and modulate cortical function by applying weak direct current over the scalp. In this review, we first introduce the underlying mechanism of action, the brief history from discovery to clinical scientific research, electrode positioning and montages, and parameter setup of tDCS. Then, we review tDCS application in clinical samples including people with drug addiction, major depression disorder, Alzheimer's disease, as well as in children...
2017: Frontiers in Psychology
https://www.readbyqxmd.com/read/28539727/bioassay-guided-isolation-and-identification-of-antioxidant-flavonoids-from-cyclotrichium-origanifolium-labill-manden-and-scheng
#18
Abdussamat Guzel, Huseyin Aksit, Mahfuz Elmastas, Ramazan Erenler
BACKGROUND: Medicinal and aromatic plants play a significant role in drug discovery and development process. Flavonoids, revealing a wide spectrum of biological activities, extensively found in plants are important secondary metabolites. MATERIALS AND METHODS: Aerial parts of Cyclotrichium origanifolium were collected, dried, and boiled in water then extracted with hexane, ethyl acetate, and n-butanol. Total phenolic content, DPPH(•) scavenging activity, reducing power (FRAP) activity, and ABTS(•+) scavenging activity assays were applied for all extracts...
April 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/28539554/investigation-of-the-pathogenesis-of-autoimmune-diseases-by-ips-cells
#19
Bunki Natsumoto, Hirofumi Shoda, Keishi Fujio, Makoto Otsu, Kazuhiko Yamamoto
  The pluripotent stem cells have a self-renewal ability and can be differentiated into theoretically all of cell types. The induced pluripotent stem (iPS) cells overcame the ethical problems of the human embryonic stem (ES) cell, and enable pathologic analysis of intractable diseases and drug discovery. The in vitro disease model using disease-specific iPS cells enables repeated analyses of human cells without influence of environment factors. Even though autoimmune diseases are polygenic diseases, autoimmune disease-specific iPS cells are thought to be a promising tool for analyzing the pathogenesis of the diseases and drug discovery in future...
2017: Nihon Rinshō Men'eki Gakkai Kaishi, Japanese Journal of Clinical Immunology
https://www.readbyqxmd.com/read/28539262/synthetic-anti-endotoxin-peptides-inhibit-cytoplasmic-lps-mediated-responses
#20
Anja Pfalzgraff, Lena Heinbockel, Qi Su, Klaus Brandenburg, Günther Weindl
Toll-like receptor (TLR) 4-independent recognition of lipopolysaccharide (LPS) in the cytosol by inflammatory caspases leads to non-canonical inflammasome activation and induction of IL-1 secretion and pyroptosis. The discovery of this novel mechanism has potential implications for the development of effective drugs to treat sepsis since LPS-mediated hyperactivation of caspases is critically involved in endotoxic shock. Previously, we demonstrated that Pep19-2.5, a synthetic anti-endotoxin peptide, efficiently neutralises pathogenicity factors of Gram-negative and Gram-positive bacteria and protects against sepsis in vivo...
May 21, 2017: Biochemical Pharmacology
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