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https://www.readbyqxmd.com/read/28435527/discovery-of-highly-potent-2-sulfonyl-pyrimidinyl-derivatives-for-apoptosis-inhibition-and-ischemia-treatment
#1
Li Li, Xian Jiang, Shaoqiang Huang, Zhengxin Ying, Zhaolan Zhang, Chenjie Pan, Sisi Li, Xiaodong Wang, Zhiyuan Zhang
A series of 2-sulfonyl-pyrimidinyl derivatives was developed as apoptosis inhibitors. These represent the first class of apoptosis inhibitors that function through stabilizing mitochondrial respiratory complex II. Starting from a phenotypic screen hit with micromolar activity, we optimized the cellular apoptosis inhibition activity of 2-sulfonyl-pyrimidinyl derivatives to picomolar level (compound 42, also named as TC9-305). The therapeutic potential of these new apoptosis inhibitors was further demonstrated by their neuroprotective effect on an ischemic animal model...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28432090/international-variations-in-clinical-practice-guidelines-for-palliative-sedation-a-systematic-review
#2
REVIEW
Ebun Abarshi, Judith Rietjens, Lenzo Robijn, Augusto Caraceni, Sheila Payne, Luc Deliens, Lieve Van den Block
OBJECTIVES: Palliative sedation is a highly debated medical practice, particularly regarding its proper use in end-of-life care. Worldwide, guidelines are used to standardise care and regulate this practice. In this review, we identify and compare national/regional clinical practice guidelines on palliative sedation against the European Association for Palliative Care (EAPC) palliative sedation Framework and assess the developmental quality of these guidelines using the Appraisal Guideline Research and Evaluation (AGREE II) instrument...
April 20, 2017: BMJ Supportive & Palliative Care
https://www.readbyqxmd.com/read/28430158/identification-of-tight-binding-plasmepsin-ii-and-falcipain-2-inhibitors-in-aqueous-extracts-of-marine-invertebrates-by-the-combination-of-enzymatic-and-interaction-based-assays
#3
Emir Salas-Sarduy, Yasel Guerra, Giovanni Covaleda Cortés, Francesc Xavier Avilés, María A Chávez Planes
Natural products from marine origin constitute a very promising and underexplored source of interesting compounds for modern biotechnological and pharmaceutical industries. However, their evaluation is quite challenging and requires specifically designed assays to reliably identify the compounds of interest in a highly heterogeneous and interfering context. In the present study, we describe a general strategy for the confident identification of tight-binding protease inhibitors in the aqueous extracts of 62 Cuban marine invertebrates, using Plasmodium falciparum hemoglobinases Plasmepsin II and Falcipain 2 as model enzymes...
April 21, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28427007/novel-and-revisited-approaches-in-antituberculosis-drug-discovery
#4
REVIEW
Jennifer Herrmann, Jan Rybniker, Rolf Müller
The increasing prevalence of multidrug-resistant Mycobacterium tuberculosis (Mtb) necessitates the discovery and development of novel drugs against tuberculosis. In this review, we focus on two recent approaches that led to the discovery of promising antitubercular compound classes: (I) Hits derived from large compound library screens are increasingly difficult to translate into clinical application; this in turn fostered the development of innovative screening methods. (II) An alternative strategy towards high-quality hits and leads is to evaluate chemically diverse scaffolds which can be found among natural products...
April 17, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28425495/the-biglen-gpr171-peptide-receptor-system-within-the-basolateral-amygdala-regulates-anxiety-like-behavior-and-contextual-fear-conditioning
#5
Erin N Bobeck, Ivone Gomes, Darlene Pena, Kirstie A Cummings, Roger L Clem, Mihaly Mezei, Lakshmi A Devi
Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and other mood disorders. Since GPR171, a recently deorphanized receptor for the abundant neuropeptide BigLEN, is expressed in the BLA, we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds. One of the hits, MS0021570_1, was identified as a GPR171 antagonist based on its ability to block (i) BigLEN-mediated activation of GPR171 in heterologous cells, (ii) BigLEN-mediated hyperpolarization of BLA pyramidal neurons, and (iii) feeding induced by DREADD-mediated activation of BigLEN containing AgRP neurons in the arcuate nucleus...
April 20, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28410536/the-influence-of-ball-swing-on-the-timing-and-coordination-of-a-natural-interceptive-task
#6
Vishnu Sarpeshkar, David L Mann, Wayne Spratford, Bruce Abernethy
Successful interception relies on the use of perceptual information to accurately guide an efficient movement strategy that allows performers to be placed at the right place at the right time. Although previous studies have highlighted the differences in the timing and coordination of movement that underpin interceptive expertise, very little is known about how these movement patterns are adapted when intercepting targets that follow a curvilinear flight-path. The aim of this study was to examine how curvilinear ball-trajectories influence movement patterns when intercepting a fast-moving target...
April 11, 2017: Human Movement Science
https://www.readbyqxmd.com/read/28397890/discovery-and-optimization-of-selective-inhibitors-of-protein-arginine-methyltransferase-5-by-docking-based-virtual-screening
#7
Yan Ye, Bidong Zhang, Ruifeng Mao, Chenhua Zhang, Yulan Wang, Jing Xing, Yu-Chih Liu, Xiaomin Luo, Hong Ding, Yaxi Yang, Bing Zhou, Hualiang Jiang, Kaixian Chen, Cheng Luo, Mingyue Zheng
Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT enzyme critical for diverse cellular processes and different types of cancers. Many efforts have been made to discover novel scaffold PRMT5 inhibitors. Herein, we report the discovery of DC_P33 as a hit compound of PRMT5 inhibitor, identified by molecular docking based virtual screening and (3)H-labeled radioactive methylation assays. Structure-activity relationship (SAR) analysis was performed on the analogs of DC_P33 and then structural modifications were done to improve its activity...
April 11, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28390229/discovery-of-4-amino-3-arylsulfoquinolines-a-novel-non-acetylenic-chemotype-of-metabotropic-glutamate-5-mglu5-receptor-negative-allosteric-modulators
#8
János Galambos, Attila Bielik, Gábor Wágner, György Domány, János Kóti, Zoltán Béni, Áron Szigetvári, Zsuzsanna Sánta, Zoltán Orgován, Amrita Bobok, Béla Kiss, Mónika L Mikó-Bakk, Mónika Vastag, Katalin Sághy, Mikhail Krasavin, Krisztina Gál, István Greiner, Zsolt Szombathelyi, György M Keserű
Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo...
March 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28388665/dose-response-relationships-for-environmentally-mediated-infectious-disease-transmission-models
#9
Andrew F Brouwer, Mark H Weir, Marisa C Eisenberg, Rafael Meza, Joseph N S Eisenberg
Environmentally mediated infectious disease transmission models provide a mechanistic approach to examining environmental interventions for outbreaks, such as water treatment or surface decontamination. The shift from the classical SIR framework to one incorporating the environment requires codifying the relationship between exposure to environmental pathogens and infection, i.e. the dose-response relationship. Much of the work characterizing the functional forms of dose-response relationships has used statistical fit to experimental data...
April 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28377530/topoisomerase-ii-inhibitors-induce-dna-damage-dependent-interferon-responses-circumventing-ebola-virus-immune-evasion
#10
Priya Luthra, Sebastian Aguirre, Benjamin C Yen, Colette A Pietzsch, Maria T Sanchez-Aparicio, Bersabeh Tigabu, Lorraine K Morlock, Adolfo García-Sastre, Daisy W Leung, Noelle S Williams, Ana Fernandez-Sesma, Alexander Bukreyev, Christopher F Basler
Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs...
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28352178/attention-deficit-hyperactivity-disorder-in-elementary-school-students-in-shantou-china-prevalence-subtypes-and-influencing-factors
#11
Yanhong Huang, Shaoxiong Zheng, Chongtao Xu, Kun Lin, Kusheng Wu, Maochun Zheng, Jie Zhang, Haiyun Xu
Attention-deficit hyperactivity disorder (ADHD) is a frequent childhood-onset psychiatric condition and categorized into three subtypes of predominantly inattentive (ADHD-I), hyperactive impulsive (ADHD-H), and combined (ADHD-C). The prevalence and subtypes of ADHD vary considerably. The primary aim of this study was to provide a prevalence estimate of ADHD in elementary school students living in Shantou, a district of China, and in addition to examine the influence of informants, age, and gender on the prevalence...
2017: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/28331172/an-anti-coagulation-conundrum-implantation-of-total-artificial-heart-in-a-patient-with-heparin-induced-thrombocytopenia-type-ii
#12
Theodore J Cios, Yuliana Salamanca-Padilla, Dmitri Guvakov
BACKGROUND Heparin-induced thrombocytopenia (HIT) is a rare but life-threatening complication of heparin administration. It can present a major clinical dilemma for physicians caring for patients requiring life-saving urgent or emergent cardiac surgery. Studies have been published examining the use of alternative anticoagulants for patients undergoing cardiopulmonary bypass (CPB), however, evidence does not clearly support any particular approach. Presently, there are no large-scale, prospective randomized studies examining the impact of alternative anticoagulants on clinical outcomes for HIT-positive patients requiring cardiac surgery...
March 23, 2017: American Journal of Case Reports
https://www.readbyqxmd.com/read/28283929/molecular-docking-studies-to-explore-potential-binding-pockets-and-inhibitors-for-chikungunya-virus-envelope-glycoproteins
#13
Phuong T V Nguyen, Haibo Yu, Paul A Keller
The chikungunya virus (CHIKV) envelope glycoproteins are considered important potential targets for anti-CHIKV drug discovery due to their crucial roles in virus attachment and virus entry. In this study, using two available crystal structures of the immature and mature forms of envelope glycoproteins, virtual screenings based on blind dockings and focused dockings were carried out to identify potential binding pockets and hit compounds for the virus. The chemical library database of compounds, NCI Diversity Set II, was used in these docking studies...
March 11, 2017: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/28258977/different-sensitivities-of-photosystem-ii-in-green-algae-and-cyanobacteria-to-phenylurea-and-phenol-type-herbicides-effect-on-electron-donor-side
#14
Ekaterina K Yotsova, Martin A Stefanov, Anelia G Dobrikova, Emilia L Apostolova
The effects of short-term treatment with phenylurea (DCMU, isoproturon) and phenol-type (ioxynil) herbicides on the green alga Chlorella kessleri and the cyanobacterium Synechocystis salina with different organizations of photosystem II (PSII) were investigated using pulse amplitude modulated (PAM) chlorophyll fluorescence and photosynthetic oxygen evolution measured by polarographic oxygen electrodes (Clark-type and Joliot-type). The photosynthetic oxygen evolution showed stronger inhibition than the PSII photochemistry...
March 4, 2017: Zeitschrift Für Naturforschung. C, A Journal of Biosciences
https://www.readbyqxmd.com/read/28251664/preservation-of-skeletal-muscle-mitochondrial-content-in-older-adults-relationship-between-mitochondria-fibre-type-and-high-intensity-exercise-training
#15
Victoria L Wyckelsma, Itamar Levinger, Michael J McKenna, Luke E Formosa, Michael T Ryan, Aaron C Petersen, Mitchell J Anderson, Robyn M Murphy
KEY POINTS: Ageing is associated with an upregulation of mitochondrial dynamics proteins mitofusin 2 (Mfn2) and mitochondrial dynamics protein 49 (MiD49) in human skeletal muscle with the increased abundance of Mfn2 being exclusive to type II muscle fibres. These changes occur despite a similar content of mitochondria, as measured by COXIV, NDUFA9 and complexes in their native states (Blue Native PAGE). Following 12 weeks of high-intensity training (HIT), older adults exhibit a robust increase in mitochondria content, while there is a decline in Mfn2 in type II fibres...
March 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28246189/aee788-inhibits-basal-body-assembly-and-blocks-dna-replication-in-the-african-trypanosome
#16
Catherine Sullenberger, Daniel Pique, Yuko Ogata, Kojo Mensa-Wilmot
Trypanosoma brucei causes human African trypanosomiasis (HAT). The pyrrolopyrimidine AEE788 (a hit for anti-HAT drug discovery) associates with three trypanosome protein kinases. Herein we delineate the effects of AEE788 on T. brucei using chemical biology strategies. AEE788 treatment inhibits DNA replication in the kinetoplast (mitochondrial nucleoid) and nucleus. In addition, AEE788 blocks duplication of the basal body and the bilobe without affecting mitosis. Thus, AEE788 prevents entry into S phase of the cell division cycle...
February 28, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28245710/diabetes-and-pulmonary-tuberculosis-a-global-overview-with-special-focus-on-the-situation-in-asian-countries-with-high-tb-dm-burden
#17
Chunlan Zheng, Minhui Hu, Feng Gao
BACKGROUND: The double burden of tuberculosis (TB) and diabetes mellitus (DM) is hitting certain Asian countries harder than other areas. In a global estimate, 15% of all TB cases could be attributable to DM, with 40% of those cases coming from India and China. Many other countries of South, East, and South-East Asia are of particular concern given their TB burdens, large projected increases in DM prevalence, and population size. OBJECTIVE: In this narrative review, we aimed to: (i) give an overall insight into the evidence on TB-DM epidemiology from high double burden Asian countries, (ii) present the evidence on bi-directional screening implementation in this region, (iii) discuss possible factors related to higher TB susceptibility of Asian diabetic patients, and (iv) identify TB-DM comorbidity treatment challenges...
2017: Global Health Action
https://www.readbyqxmd.com/read/28242581/identification-of-potent-virtual-leads-and-adme-prediction-of-isoxazolidine-podophyllotoxin-derivatives-as-topoisomerase-ii-and-tubulin-inhibitors
#18
Majdi M Bkhaitan, Agha Zeeshan Mirza, Hina Shamshad, Hamed I Ali
Towards the design of new class of podophyllotoxin to target topoisomerase II and tubulin as substantial target in cancer therapy, a series of isoxazolidine podophyllotoxin derivatives were designed. Topoisomerase in complex with etoposide and four β-tubulin in complex with zampanolide, taxol, vinblastine or colchicine were used as targets using GOLD5.2.2 as a docking module. The revealed key structural features of the highest fitness into tubulin domain have been explained as follows: (1) trans orientation of the lactone (ring D) with 5a-β, 8a-α configuration; (2) dioxolane in ring A; (3) free rotation of ring E; (4) α (R) or β (S) configuration has equal fitness in position 5; (5) 4'-OMe; (6) phosphoramide linkage; (7) ethylene bridge between the phosphate and isoxazolidine ring; (8) benzyl moiety at N(2)-position of isoxazolidine ring; and (9) position 5 of isoxazolidine ring accommodated with 6-bromo-9H-purine, 2-amino-6H-purin-6-one, or N-(2-oxopyrimidin-4-yl) acetamide...
May 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28241943/the-impact-of-health-information-technology-on-organ-transplant-care-a-systematic-review
#19
REVIEW
Zahra Niazkhani, Habibollah Pirnejad, Parviz Rashidi Khazaee
BACKGROUND: Health Information Technology (HIT) has a potential to promote transplant care. However, a systematic appraisal on how HIT application has so far affected transplant care is greatly missing from the literature. We systematically reviewed trials that evaluated HIT impact on process and patient outcomes as well as costs in organ transplant care. METHODS: A systematic search was conducted in OVID versions of MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane, and IEEE databases from January 1990 to December 2015...
April 2017: International Journal of Medical Informatics
https://www.readbyqxmd.com/read/28240184/from-protein-structure-to-small-molecules-recent-advances-and-applications-to-fragment-based-drug-discovery
#20
Leonardo G Ferreira, Adriano D Andricopulo
Fragment-based drug discovery (FBDD) is a broadly used strategy in structure-guided ligand design, whereby low-molecular weight hits move from lead-like to drug-like compounds. Over the past 15 years, an increasingly important role of the integration of these strategies into industrial and academic research platforms has been successfully established, allowing outstanding contributions to drug discovery. One important factor for the current prominence of FBDD is the better coverage of the chemical space provided by fragment-like libraries...
February 24, 2017: Current Topics in Medicinal Chemistry
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