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https://www.readbyqxmd.com/read/27914058/osprey-predicts-resistance-mutations-using-positive-and-negative-computational-protein-design
#1
Adegoke Ojewole, Anna Lowegard, Pablo Gainza, Stephanie M Reeve, Ivelin Georgiev, Amy C Anderson, Bruce R Donald
Drug resistance in protein targets is an increasingly common phenomenon that reduces the efficacy of both existing and new antibiotics. However, knowledge of future resistance mutations during pre-clinical phases of drug development would enable the design of novel antibiotics that are robust against not only known resistant mutants, but also against those that have not yet been clinically observed. Computational structure-based protein design (CSPD) is a transformative field that enables the prediction of protein sequences with desired biochemical properties such as binding affinity and specificity to a target...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914004/hybrid-receptor-bound-mm-gbsa-per-residue-energy-based-pharmacophore-modelling-enhanced-approach-for-identification-of-selective-lta4h-inhibitors-as-potential-anti-inflammatory-drugs
#2
Patrick Appiah-Kubi, Mahmoud Soliman
Leukotriene A4 hydrolase has been identified as an enzyme with dual anti- and pro-inflammatory role, thus, the conversion of leukotriene to leukotriene B4 in the initiation stage of inflammation and the removal of the chemotactic Pro-Gly-Pro tripeptide. These findings make leukotriene A4 hydrolase an attractive drug target: suggesting an innovative approach towards the identification and design of novel class of compounds that can selectively inhibit leukotriene B4 synthesis while sparing the aminopeptidase activity...
December 2, 2016: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27913794/tlr-ligands-but-not-modulators-of-histone-modifiers-can-induce-the-complex-immune-response-pattern-of-endotoxin-tolerance-in-mammary-epithelial-cells
#3
Juliane Günther, Wolfram Petzl, Holm Zerbe, Hans-Joachim Schuberth, Hans-Martin Seyfert
Excessive stimulation of the TLR4 axis through LPS reduces the expression of some cytokine genes in immune cells, while stimulating the expression of immune defense genes during a subsequent bacterial infection. This endotoxin tolerance (ET) is mediated via epigenetic mechanisms. Priming the udder of cows with LPS was shown to induce ET in mammary epithelial cells (MEC), thereby protecting the udder against reinfection for some time. Seeking alternatives to LPS priming we tried to elicit ET by priming MEC with either lipopeptide (Pam2CSK4) via the TLR2/6 axis or inhibitors of histone-modifying enzymes...
December 1, 2016: Innate Immunity
https://www.readbyqxmd.com/read/27913583/epigenetic-control-of-microsomal-prostaglandin-e-synthase-1-by-hdac-mediated-recruitment-of-p300
#4
Christian Fork, Andrea E Vasconez, Patrick Janetzko, Carlo Angioni, Yannick Schreiber, Nerea Ferreiros, Gerd Geisslinger, Matthias S Leisegang, Dieter Steinhilber, Ralf P Brandes
: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medicine to treat pain, fever, inflammation and to inhibit platelet function. Understanding the expression regulation of enzymes of the prostanoid pathway is of great medical relevance. Histone acetylation crucially controls gene expression. We set out to identify the impact of histone deacetylases (HDACs) on the generation of prostanoids and examine the consequences on vascular function. Inhibition of HDACs (HDACi) with the pan HDAC inhibitor SAHA attenuated prostaglandin E2 (PGE2) generation in the murine vasculature and in human vascular smooth muscle cells...
December 2, 2016: Journal of Lipid Research
https://www.readbyqxmd.com/read/27913306/effect-of-bradykinin-receptor-antagonism-on-ace-inhibitor-associated-angioedema
#5
Brittany T Straka, Claudia E Ramirez, James B Byrd, Elizabeth Stone, Alencia Woodard-Grice, Hui Nian, Chang Yu, Aleena Banerji, Nancy J Brown
BACKGROUND: The B2 receptor antagonist icatibant is approved for treatment of attacks of hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema in one study of European patients. METHODS: Patients with ACE inhibitor-associated angioedema (defined as swelling of lips, tongue, pharynx or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through September 2015 and at Massachusetts General Hospital in 2012...
November 29, 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27913271/histone-deacetylases-hdac-in-physiological-and-pathological-bone-remodelling
#6
REVIEW
M D Cantley, A C W Zannettino, P M Bartold, D P Fairlie, D R Haynes
Histone deacetylases (HDACs)(2) play important roles in the epigenetic regulation of gene expression in cells and are emerging therapeutic targets for treating a wide range of diseases. HDAC inhibitors (HDACi)(3) that act on multiple HDAC enzymes have been used clinically to treat a number of solid and hematological malignancies. HDACi are currently being studied also for their efficacy in non-malignant diseases, including pathologic bone loss, but this has necessitated a better understanding of the roles of individual HDAC enzymes, particularly the eleven zinc-containing isozymes...
November 29, 2016: Bone
https://www.readbyqxmd.com/read/27912890/persistence-of-123-i-mibg-prognostic-capability-in-relation-to-medical-therapy-in-heart-failure-from-the-admire-hf-trial
#7
Ileana L Piña, Peter Carson, JoAnn Lindenfeld, W Tad Archambault, Arnold F Jacobson
(123)I-mIBG imaging has been evaluated to assess sympathetic function and prognosis in heart failure (HF). However, the effect of combined HF medical therapies on (123)I-mIBG uptake and its prognostic significance has not been previously examined. This analysis examined the relation between the intensity of guideline-directed HF medical therapy and global (123)I-mIBG cardiac uptake in the AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) database. A second objective was to investigate whether this guideline-based therapy, measured by total medication doses, had the expected effect on outcome, that is, that patients with higher (123)I-mIBG cardiac uptake and more intensive medical therapy had the fewest outcome events...
October 31, 2016: American Journal of Cardiology
https://www.readbyqxmd.com/read/27912879/how-do-the-alkaloids-emetine-and-homoharringtonine-kill-trypanosomes-an-insight-into-their-molecular-modes-of-action
#8
Sonja Krstin, Tamer Mohamed, Xiaojuan Wang, Michael Wink
BACKGROUND: Although Trypanosoma brucei causes deadly sleeping sickness, the number of the registered medications is rather limited. Some plant alkaloids are potent trypanocidal agents. PURPOSE: In this study, we wanted to elucidate the molecular modes of trypanocidal activity of the alkaloids emetine and homoharringtonine against Trypanosoma brucei brucei. METHODS: We investigated the activity of both alkaloids regarding growth recovery from alkaloid-induced stress...
December 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/27912149/didymin-ameliorates-hepatic-injury-through-inhibition-of-mapk-and-nf-%C3%AE%C2%BAb-pathways-by-up-regulating-rkip-expression
#9
Quanfang Huang, Facheng Bai, Jinlan Nie, Shengjuan Lu, Chunyuang Lu, Xunshuai Zhu, Lang Zhuo, Xing Lin
A flavone was isolated from Origanum vulgare and identified as didymin (O. vulgare didymin, OVD). The protective effect and mechanism of OVD on acute liver injury was then assessed in vivo and in vitro. Our results showed that OVD significantly alleviated CCl4-induced liver injury in mice and markedly decreased serum ALT and AST activities. OVD treatment significantly reduced CYP2E1 activity, lipid peroxidation level, ROS generation, NO production and pro-inflammatory cytokines (such as TNF-α, IL-6 and IL-1β) in liver tissues and RAW 264...
November 29, 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27911230/bromodomain-inhibitors-and-cancer-therapy-from-structures-to-applications
#10
Montserrat Pérez-Salvia, Manel Esteller
Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are "writers", "erasers", or "readers" of histone modification marks are common. Bromodomains are "readers" that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains...
December 2, 2016: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/27910729/identification-of-cytochrome-p450s-involved-in-the-metabolism-of-6-benzyl-1-benzyloxymethyl-5-iodouracil-w-1-using-human-recombinant-enzymes-and-rat-liver-microsomes-in-vitro
#11
Ying-Yuan Lu, Hai-Xu Cheng, Xin Wang, Xiao-Wei Wang, Jun-Yi Liu, Pu Li, Ya-Qing Lou, Jun Li, Chuang Lu, Guo-Liang Zhang
1. The aim of this study was to identify the hepatic metabolic enzymes, which involved in the biotransformation of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor (NNRTIs) in rat and human in vitro. 2. The parent drug of W-1 was incubated with RLMs or recombinant CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5, respectively) in the presence or absence of NADPH regenerating system. The metabolites of W-1 were analyzed with liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS)...
December 2, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27910199/reverse-phase-compatible-tlc-bioautography-for-detection-of-tyrosinase-inhibitors
#12
Paula García, I Ayelen Ramallo, Ricardo L E Furlan
INTRODUCTION: Reverse phase chromatography and bioautographic assays are key tools for natural product bioguided isolation; however, their direct coupling has not been fully achieved. OBJECTIVES: To develop a bioautographic assay to detect tyrosinase inhibitors present in complex matrices sorbed on reverse phase (RP) TLC-plates that can be used for bioguided isolation of bioactive compounds. METHODS: Enzyme gel entrapment with an amphiphilic copolymer was used for assay development...
December 2, 2016: Phytochemical Analysis: PCA
https://www.readbyqxmd.com/read/27909955/suppressive-effects-of-dabrafenib%C3%A2-on-endothelial-protein-c-receptor-shedding
#13
Sae-Kwang Ku, Jongdoo Kim, Sang Chan Kim, Jong-Sup Bae
Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). Dabrafenib (DAB) is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. However, little is known about the effects of DAB on EPCR shedding. We investigated this issue by monitoring the effects of DAB on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α-, interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism...
December 1, 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27909846/benzimidazole-inhibitors-of-protein-kinase-ck2-potently-inhibit-the-activity-of-atypical-protein-kinase-rio1
#14
Konrad Kubiński, Maciej Masłyk, Andrzej Orzeszko
Benzimidazole derivatives of 5,6-dichlorobenzimidazole 1-β-D-ribofuranoside (DRB) comprise the important class of protein kinase CK2 inhibitors. Depending on the structure, benzimidazoles inhibit CK2 with different selectivity and potency. Besides CK2, the compounds can inhibit, with similar activity, other classical eukaryotic protein kinases (e.g. PIM, DYRK, and PKD). The present results show that a majority of the most common CK2 inhibitors can affect the atypical kinase Rio1 in a nanomolar range. Kinetic data confirmed the mode of action of benzimidazoles as typical ATP-competitive inhibitors...
December 1, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27909234/a-high-throughput-screening-strategy-for-development-of-rnf8-ubc13-protein-protein-interaction-inhibitors
#15
Elisabeth Weber, Ina Rothenaigner, Stefanie Brandner, Kamyar Hadian, Kenji Schorpp
The ubiquitin-proteasome system plays an essential role in a broad range of cellular signaling pathways. Ubiquitination is a posttranslational protein modification that involves the action of an enzymatic cascade (E1, E2, and E3 enzymes) for the covalent attachment of ubiquitin to target proteins. The emerging knowledge of the molecular mechanisms and correlation of deregulation of the ubiquitin system in human diseases is uncovering new opportunities for therapeutics development. The E3 ligase RNF8 acts in cooperation with the heterodimeric E2 enzyme Ubc13/Uev1a to generate ubiquitin conjugates at the sides of DNA double-strand breaks, and recent findings suggest RNF8 as a potential therapeutic target for the treatment of breast cancer...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27908822/how-admission-to-a-vascular-surgery-department-improves-medical-treatment-in-patients-with-lower-extremity-peripheral-arterial-disease
#16
M Thiney, N Della Schiava, P Feugier, P Lermusiaux, J Ninet, A Millon, A Long
OBJECTIVES: All patients with lower extremity peripheral arterial disease (LE-PAD) should benefit from recommended pharmacologic therapies including antiplatelet agents, angiotensin converting enzyme (ACE) inhibitors or Angiotensin receptor blockers (ARBs), and HMG-CoA-reductase inhibitors (statins). In the present study, this triple therapy was defined as the best medical treatment. This study was designed to determine the number of patients who received best medical treatment at admission and at discharge from a vascular surgery department...
November 28, 2016: Annals of Vascular Surgery
https://www.readbyqxmd.com/read/27908752/n-propargylpiperidines-with-naphthalene-2-carboxamide-or-naphthalene-2-sulfonamide-moieties-potential-multifunctional-anti-alzheimer-s-agents
#17
Urban Košak, Damijan Knez, Nicolas Coquelle, Boris Brus, Anja Pišlar, Florian Nachon, Xavier Brazzolotto, Janko Kos, Jacques-Philippe Colletier, Stanislav Gobec
In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines...
November 19, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908544/inhibition-of-cartilage-degradation-and-suppression-of-pge2-and-mmps-expression-by-pomegranate-fruit-extract-in-a-model-of-posttraumatic-osteoarthritis
#18
Nahid Akhtar, Nazir M Khan, Omer S Ashruf, Tariq M Haqqi
OBJECTIVE: Osteoarthritis (OA) is characterized by cartilage degradation in the affected joints. Pomegranate fruit extract (PFE) inhibits cartilage degradation in vitro. The aim of this study was to determine whether oral consumption of PFE inhibits disease progression in rabbits with surgically induced OA. METHODS: OA was surgically induced in the tibiofemoral joints of adult New Zealand White rabbits. In one group, animals were fed PFE in water for 8 wk postsurgery...
January 2017: Nutrition
https://www.readbyqxmd.com/read/27908347/prognostic-implications-of-changes-in-n-terminal-pro-b-type-natriuretic-peptide-in-patients-with-heart-failure
#19
Michael R Zile, Brian L Claggett, Margaret F Prescott, John J V McMurray, Milton Packer, Jean L Rouleau, Karl Swedberg, Akshay S Desai, Jianjian Gong, Victor C Shi, Scott D Solomon
BACKGROUND: Natriuretic peptides (NP) have prognostic value in heart failure (HF), although the clinical importance of changes in NP from baseline is unclear. OBJECTIVES: The authors assessed whether a reduction in N-terminal pro-B-type NP (NT-proBNP) was associated with a decrease in HF hospitalization and cardiovascular mortality (primary endpoint) in patients with HF and reduced ejection fraction, whether treatment with sacubitril/valsartan reduced NT-proBNP below specific partition values more than enalapril, and whether the relationship between changes in NT-proBNP and changes in the primary endpoint were dependent on assigned treatment...
December 6, 2016: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/27907877/synthesis-alkaline-phosphatase-inhibition-studies-and-molecular-docking-of-novel-derivatives-of-4-quinolones
#20
Mariia Miliutina, Syeda Abida Ejaz, Shafi Ullah Khan, Viktor O Iaroshenko, Alexander Villinger, Jamshed Iqbal, Peter Langer
New and convenient methods for the functionalization of the 4-quinolone scaffold at positions C-1, C-3 and C-6 were developed. The 4-quinolone derivatives were evaluated for their inhibitory potential on alkaline phosphatase isozymes. Most of the compounds exhibit excellent inhibitory activity and moderate selectivity. The IC50 values on tissue non-specific alkaline phosphatase (TNAP) were in the range of 1.34 ± 0.11 to 44.80 ± 2.34 μM, while the values on intestinal alkaline phosphatase (IAP) were in the range of 1...
November 17, 2016: European Journal of Medicinal Chemistry
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