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https://www.readbyqxmd.com/read/28319812/exploring-sequence-space-harnessing-chemical-and-biological-diversity-towards-new-peptide-leads
#1
REVIEW
Richard Obexer, Louise J Walport, Hiroaki Suga
From their early roots in natural products, peptides now represent an expanding class of novel drugs. Their modular structures make them ideal candidates for pooled library screening approaches. Key technologies for library generation and screening, such as SICLOPPS, phage display and mRNA display, give unparalleled access to tight binding peptides. Through combination with genetic code reprogramming and chemical modifications, access to more natural product-like libraries, spanning non-canonical peptide space, is readily achievable...
March 17, 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28319113/combinatorial-crispr-cas9-screens-for-de-novo-mapping-of-genetic-interactions
#2
John Paul Shen, Dongxin Zhao, Roman Sasik, Jens Luebeck, Amanda Birmingham, Ana Bojorquez-Gomez, Katherine Licon, Kristin Klepper, Daniel Pekin, Alex N Beckett, Kyle Salinas Sanchez, Alex Thomas, Chih-Chung Kuo, Dan Du, Assen Roguev, Nathan E Lewis, Aaron N Chang, Jason F Kreisberg, Nevan Krogan, Lei Qi, Trey Ideker, Prashant Mali
We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies...
March 20, 2017: Nature Methods
https://www.readbyqxmd.com/read/28319085/synergistic-drug-combinations-for-cancer-identified-in-a-crispr-screen-for-pairwise-genetic-interactions
#3
Kyuho Han, Edwin E Jeng, Gaelen T Hess, David W Morgens, Amy Li, Michael C Bassik
Identification of effective combination therapies is critical to address the emergence of drug-resistant cancers, but direct screening of all possible drug combinations is infeasible. Here we introduce a CRISPR-based double knockout (CDKO) system that improves the efficiency of combinatorial genetic screening using an effective strategy for cloning and sequencing paired single guide RNA (sgRNA) libraries and a robust statistical scoring method for calculating genetic interactions (GIs) from CRISPR-deleted gene pairs...
March 20, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28318947/docking-synthesis-and-antimalarial-activity-of-novel-4-anilinoquinoline-derivatives
#4
Shilpa Vijayaraghavan, Supriya Mahajan
A series of 4-anilinoquinoline triazine derivatives were designed, synthesized and screened for in vivo antimalarial activity against a chloroquine-sensitive strain of Plasmodium berghei. The compounds were further subjected to in vitro antimalarial activity against chloroquine-resistant W2 strain of Plasmodium falciparum and β-haematin inhibition studies. All the compounds exhibited in vivo antimalarial activity better than that shown by the standard drug, chloroquine. Twelve out of fifteen compounds showed better inhibition than that of chloroquine against chloroquine-resistant W2 strain of Plasmodium falciparum...
March 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28318945/identification-and-structure-activity-relationships-of-quinoline-tertiary-alcohol-modulators-of-ror%C3%AE-t
#5
David A Kummer, Maxwell D Cummings, Marta Abad, Joseph Barbay, Glenda Castro, Ronald Wolin, Kevin D Kreutter, Umar Maharoof, Cynthia Milligan, Rachel Nishimura, Joan Pierce, Celine Schalk-Hihi, John Spurlino, Maud Urbanski, Hariharan Venkatesan, Aihua Wang, Craig Woods, Xiaohua Xue, James P Edwards, Anne M Fourie, Kristi Leonard
A high-throughput screen of the ligand binding domain of the nuclear receptor retinoic acid-related orphan receptor gamma t (RORγt) employing a thermal shift assay yielded a quinoline tertiary alcohol hit. Optimization of the 2-, 3- and 4-positions of the quinoline core using structure-activity relationships and structure-based drug design methods led to the discovery of a series of modulators with improved RORγt inhibitory potency and inverse agonism properties.
February 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28318376/advances-in-on-chip-vascularization
#6
Kristina Haase, Roger D Kamm
Microfluidics is invaluable for studying microvasculature, development of organ-on-chip models and engineering microtissues. Microfluidic design can cleverly control geometry, biochemical gradients and mechanical stimuli, such as shear and interstitial flow, to more closely mimic in vivo conditions. In vitro vascular networks are generated by two distinct approaches: via endothelial-lined patterned channels, or by self-assembled networks. Each system has its own benefits and is amenable to the study of angiogenesis, vasculogenesis and cancer metastasis...
March 20, 2017: Regenerative Medicine
https://www.readbyqxmd.com/read/28318223/high-throughput-dual-screening-method-for-ras-activities-and-inhibitors
#7
Kari Kopra, Arjan J van Adrichem, Outi M H Salo-Ahen, Juha Peltonen, Krister Wennerberg, Harri J Härmä
Ras GTPases act as "molecular switches", alternating between inactive GDP-bound and active GTP-bound conformation. Ras-oncogenes were discovered over three decades ago, but there are still no effective therapies for Ras-driven cancers. Drug discovery strategies have so far been unsuccessful, due to a lack of suitable screening methodologies and well-defined binding pockets on the Ras proteins. Here, we addressed the former by introducing a homogeneous quenching resonance energy transfer (QRET) technique based screening strategy for Ras interfacial and competitive inhibitors...
March 20, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28317948/local-remodeling-of-synthetic-extracellular-matrix-microenvironments-by-co-cultured-endometrial-epithelial-and-stromal-cells-enables-long-term-dynamic-physiological-function
#8
Christi D Cook, Abby S Hill, Margaret Guo, Linda Stockdale, Julia P Papps, Keith B Isaacson, Douglas A Lauffenburger, Linda G Griffith
Mucosal barrier tissues, comprising a layer of tightly-bonded epithelial cells in intimate molecular communication with an underlying matrix-rich stroma containing fibroblasts and immune cells, are prominent targets for drugs against infection, chronic inflammation, and other disease processes. Although human in vitro models of such barriers are needed for mechanistic studies and drug development, differences in extracellular matrix (ECM) needs of epithelial and stromal cells hinder efforts to create such models...
March 20, 2017: Integrative Biology: Quantitative Biosciences From Nano to Macro
https://www.readbyqxmd.com/read/28317886/systems-pharmacology-based-strategy-to-screen-new-adjuvant-for-hepatitis-b-vaccine-from-traditional-chinese-medicine-ophiocordyceps-sinensis
#9
Jingbo Wang, Rui Liu, Baoxiu Liu, Yan Yang, Jun Xie, Naishuo Zhu
Adjuvants are common component for many vaccines but there are still few licensed for human use due to low efficiency or side effects. The present work adopted Systems Pharmacology analysis as a new strategy to screen adjuvants from traditional Chinese medicine. Ophiocordyceps sinensis has been used for many years in China and other Asian countries with many biological properties, but the pharmacological mechanism has not been fully elucidated. First in this study, 190 putative targets for 17 active compounds in Ophiocordyceps sinensis were retrieved and a systems pharmacology-based approach was applied to provide new insights into the pharmacological actions of the drug...
March 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28317879/a-novel-method-for-screening-adenosine-receptor-specific-agonists-for-use-in-adenosine-drug-development
#10
Karlie R Jones, Uimook Choi, Ji-Liang Gao, Robert D Thompson, Larry E Rodman, Harry L Malech, Elizabeth M Kang
Agonists that target the A1, A2A, A2B and A3 adenosine receptors have potential to be potent treatment options for a number of diseases, including autoimmune diseases, cardiovascular disease and cancer. Because each of these adenosine receptors plays a distinct role throughout the body, obtaining highly specific receptor agonists is essential. Of these receptors, the adenosine A2AR and A2BR share many sequence and structural similarities but highly differ in their responses to inflammatory stimuli. Our laboratory, using a combination of specially developed cell lines and calcium release analysis hardware, has created a new and faster method for determining specificity of synthetic adenosine agonist compounds for the A2A and A2B receptors in human cells...
March 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28317805/prevalence-and-genetic-determinant-of-drug-resistant-tuberculosis-among-patients-completing-intensive-phase-of-treatment-in-a-tertiary-referral-center-in-nigeria
#11
Aminu Bashir Mohammad, Garba Iliyasu, Abdulrazaq Garba Habib
BACKGROUND: Drug-resistant tuberculosis (DR-TB) continues to be a challenge in developing countries with poor resources. Despite the high prevalence of primary DR-TB, its routine screening prior to the treatment is not performed in public hospitals in Nigeria. Data regarding drug resistance and its genetic determinant among follow-up patients with TB are lacking in Nigeria. Hence, the aim of this study was to determine the prevalence and genetic determinant of drug resistance among the follow-up patients with TB in a tertiary hospital in Nigeria...
January 2017: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28317478/homocysteine-and-non-cardiac-vascular-disease
#12
Niki Katsiki, Pablo Perez-Martinez, Dimitri P Mikhailidis
Elevated homocysteine (Hcy) levels are predictors of cardiovascular disease (CVD). Hyperhomocysteinemia has also been associated with total and CVD mortality. However, whether Hcy is just a marker or plays a causal role in CVD remains to be elucidated. In this narrative review, we discuss the associations between Hcy and non-cardiac vascular diseases, namely stroke, peripheral artery disease (PAD), carotid artery disease, chronic kidney disease (CKD), atherosclerotic renal artery stenosis (ARAS), abdominal aortic aneurysm (AAA) and erectile dysfunction (ED)...
March 17, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28317156/synthesis-and-anticonvulsant-properties-of-new-3-3-diphenyl-2-5-dioxo-pyrrolidin-1-yl-acetamides-and-3-3-diphenyl-propionamides
#13
Jolanta Obniska, Anna Rapacz, Sabina Rybka, Małgorzata Góra, Paweł Żmudzki, Krzysztof Kamiński
The focused library of new amides derived from 3,3-diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid (2a-t) and 3,3-diphenyl-propionic acid (3a-t) as potential anticonvulsant agents was synthesized. The final products were obtained in the amidation reaction of the given carboxylic acid (2, 3) with appropriate secondary amines in the presence of carbonyldiimidazole (CDI) as a coupling reagent. The initial anticonvulsant screening was performed in mice intraperitoneally (i.p.) using the "classical" maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas the acute neurological toxicity was determined applying the rotarod test...
March 20, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28316009/safety-assessment-of-commensal-enterococci-from-dogs
#14
Ivana Kubašová, Viola Strompfová, Andrea Lauková
Enterococci form a complex, diverse, and very important group of bacteria from the technological and food safety aspect, or from the health-improving aspect as probiotics. Generally, enterococci are considered to be of low pathogenic potential, which is associated mostly with clinical strains. In these strains, production of virulence factors as well as resistance to many antimicrobial drugs could complicate treatment of nosocomial infections. Because there is a lack of information on incidence of these attributes in animal commensal enterococci, we screened 160 strains originating from feces of clinically healthy dogs in Eastern Slovakia (n = 105)...
March 18, 2017: Folia Microbiologica
https://www.readbyqxmd.com/read/28315995/ligand-based-virtual-screening-under-partial-shape-constraints
#15
Mathias M von Behren, Matthias Rarey
Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure...
March 18, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28315856/an-update-on-hla-alleles-associated-with-adverse-drug-reactions
#16
Ingrid Fricke-Galindo, Adrián LLerena, Marisol López-López
Adverse drug reactions (ADRs) are considered as an important cause of morbidity and mortality. The hypersensitivity reactions are immune-mediated ADRs, which are dose-independent, unpredictable and have been associated with several HLA alleles. The present review aimed to describe HLA alleles that have been associated with different ADRs in populations worldwide, the recommendations of regulatory agencies and pharmacoeconomic information and databases for the study of HLA alleles in pharmacogenetics. A systematic search was performed in June 2016 of articles relevant to this issue in indexed journals and in scientific databases (PubMed and PharmGKB)...
March 18, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/28315739/method-of-data-interpretation-for-the-determination-of-abuse-liability-in-rodent-self-administration-studies-under-the-fda-guidance-document
#17
David V Gauvin, Zachary J Zimmermann, Theodore J Baird
All new molecular entities that enter the CNS and exert an activity in the brain must be assessed for abuse liability prior to a New Drug Application approval by the US Food and Drug Administration. One element of the screening process is the assessment of the reinforcing properties of the drug candidate using the regulatory-preferred species, the rat. We describe one method of data review from the standard rat IV SA study design that can be used to conclude the relative abuse liability of the new drug entity...
March 15, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28315618/interaction-of-vasicine-with-calf-thymus-dna-molecular-docking-spectroscopic-and-differential-scanning-calorimetric-insights
#18
Sai Murali R S, Sai Siddhardha R S, Rajesh Babu D, Venketesh S, Basavaraju R, Nageswara Rao G
The present study brings out the interaction between vasicine, an alkaloid and Adhatoda vasica Nees with double stranded DNA. The physico-chemical interaction between small molecules and nucleic acids is a major area of focus in screening drugs against various cancers. Molecular probing in our study using Molecular Operating Environment (MOE) has revealed interaction of vasicine with DNA double helix. Here we report the interaction of vasicine with Calf thymus DNA. We present for the first time the results obtained from UV-visible, fluorescence spectroscopic and differential scanning calorimetric techniques that suggest a moderate to strong electrostatic, hydrophobic and van der Waals interactions mediating the DNA binding properties of vasicine, leading to disruption of DNA secondary structure...
March 8, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/28315465/early-preclinical-evaluation-of-dihydropyrimidin-thi-ones-as-potential-anticonvulsant-drug-candidates
#19
Mariana Matias, Gonçalo Campos, Samuel Silvestre, Amílcar Falcão, Gilberto Alves
Although significant advances are occurring in epilepsy research, about 30% of epileptic patients are still inadequately controlled by standard drug therapy. For this reason, it continues to be important to develop new chemical entities through which epilepsy could be effectively controlled. In this study, the anticonvulsant activity of forty-two dihydropyrimidin(thi)ones was explored and their efficacy was evaluated in rodents against the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole tests...
March 14, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28315327/discovery-of-a-kelch-like-ech-associated-protein-1-inhibitory-tetrapeptide-and-its-structural-characterization
#20
Satoshi Sogabe, Kotaro Sakamoto, Yusuke Kamada, Akito Kadotani, Yasunori Fukuda, Jun-Ichi Sakamoto
Keap1 constitutively binds to the transcription factor Nrf2 to promote its degradation, resulting in negative modulation of genes involved in cellular protection against oxidative stress. Keap1 is increasingly recognized as an attractive target for treating diseases involving oxidative stress, including cancer, atherosclerosis, diabetes, arthritis, and neurodegeneration. We used phage-display peptide screening to identify a tetrapeptide showing moderate binding affinity, which inhibits the interaction between Nrf2 and Keap1...
March 14, 2017: Biochemical and Biophysical Research Communications
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