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Hit II

Gayan S Jayawickrama, Alireza Nematollahi, Guanchen Sun, W Bret Church
Kynurenine aminotransferase-II (KAT-II) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that acts in the tryptophan metabolic pathway by catalyzing the transamination of kynurenine into kynurenic acid (KYNA). It is one of four isoforms in the KAT family, of which it is the primary homologue responsible for KYNA production in the mammalian brain. KAT-II is targeted for inhibition as KYNA is implicated in diseases such as schizophrenia, where it is found in elevated concentrations. Previously, many different approaches have been taken to develop KAT-II inhibitors, and herein fragment-based drug design (FBDD) approaches have been exploited to provide further lead compounds that can be designed into novel inhibitors...
March 1, 2018: SLAS Discovery
Rashmi Gupta, Carolina R Felix, Matthew P Akerman, Kate J Akerman, Cathryn A Slabber, Wenjie Wang, Jessie Adams, Lindsey N Shaw, Yuk-Ching Tse-Dinh, Orde Q Munro, Kyle H Rohde
Mycobacterium tuberculosis ( Mtb ) and the fast-growing Mycobacterium abscessus ( Mab ) are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug resistant Mtb strains and the high level of intrinsic resistance of Mab calls for novel drug scaffolds that effectively target both pathogens. In this study, we have evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase I and II, against Mab and Mtb...
February 26, 2018: Antimicrobial Agents and Chemotherapy
Ying Fu, Yi-Na Sun, Ke-Han Yi, Ming-Qiang Li, Hai-Feng Cao, Jia-Zhong Li, Fei Ye
4-Hydroxyphenylpyruvate dioxygenase (EC, HPPD) is a potent new bleaching herbicide target. Therefore, in silico structure-based virtual screening was performed in order to speed up the identification of promising HPPD inhibitors. In this study, an integrated virtual screening protocol by combining 3D-pharmacophore model, molecular docking and molecular dynamics (MD) simulation was established to find novel HPPD inhibitors from four commercial databases. 3D-pharmacophore Hypo1 model was applied to efficiently narrow potential hits...
2018: Frontiers in Chemistry
Bela Ozsvari, Federica Sotgia, Michael P Lisanti
Tri-phenyl-phosphonium (TPP) is a non-toxic chemical moiety that functionally behaves as a mitochondrial targeting signal (MTS) in living cells. Here, we explored the hypothesis that TPP-related compounds could be utilized to inhibit mitochondria in cancer stem cells (CSCs). We randomly selected 9 TPP-related compounds for screening, using an ATP depletion assay. Based on this approach, five compounds were identified as "positive hits"; two had no detectable effect on ATP production. Remarkably, this represents a >50% hit rate...
February 19, 2018: Aging
Alexander M Andrianov, Ivan A Kashyn, Alexander V Tuzikov
An integrated computational approach to in silico drug design was used to identify novel HIV-1 fusion inhibitor scaffolds mimicking broadly neutralizing antibody (bNab) 10E8 targeting the membrane proximal external region (MPER) of the HIV-1 gp41 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb 10E8 active towards the gp41 MPER segment, (ii) shape and pharmacophore-based identification of the 10E8-mimetic candidates by a web-oriented virtual screening platform pepMMsMIMIC, (iii) high-throughput docking of the identified compounds with the gp41 MPER peptide, and (iv) molecular dynamics simulations of the docked structures followed by binding free energy calculations...
January 15, 2018: Journal of Bioinformatics and Computational Biology
Rana Adnan Tahir, Sheikh Arslan Sehgal
BACKGROUND: Synapsin II regulates neurotransmitter release from mature nerve terminals and plays important role in the formation of new nerve terminals. The associations of SYN II are identified in various studies that are linked to the onset of Schizophrenia. Schizophrenia is characterized by abnormal behavior like obsession, dampening of emotions and auditory hallucination. METHODS: The bioinformatics approaches were utilized for structural modeling and docking analyses of SYN II followed by pharmacophore generation to identify potent inhibitors...
February 12, 2018: Combinatorial Chemistry & High Throughput Screening
Minghao Li, Qianqian Liu, Peihua Liu, Xiaoping Yi, Xiao Guan, Anze Yu, Longfei Liu, Feizhou Zhu
Heterozygous germline mutation of the MEN1 tumor suppressor gene is responsible for multiple endocrine neoplasia type 1. Parathyroid and thoracic neuroendocrine tumor specimens and DNA from two Han Chinese MEN1 family patients were analyzed using whole exome and Sanger sequencing. The proband (II-3) was sequentially diagnosed with pituitary adenoma, pancreatic tumor, adrenal cortical tumor, abdominal lipoma, and parathyroid adenoma during the 6-year follow-up. The son of the proband (III-6) was also diagnosed with a thoracic neuroendocrine tumor and a parathyroid adenoma during this period...
January 5, 2018: Oncotarget
Frank Erdmann, Erik Prell, Günther Jahreis, Gunter Fischer, Miroslav Malesevic
The IANUS (Induced orgANization of strUcture by matrix-assisted togethernesS) peptide array was build up on a hypothesis that two peptides from two interacting protein epitopes are also able to interact when immobilized on a solid support. This peptide-peptide interactions can be visualized by FRET effects caused by close proximity of fluorescent labeled peptide chains. The biggest advantage of this low-resolution method is that no soluble protein probe or selective antibodies are needed. We applied the IANUS peptide array to screen for peptides from a phospatase Calcineurin (CaN) that binds to regulatory domain of the nuclear factor of activated T cells (NFAT)...
February 7, 2018: Chembiochem: a European Journal of Chemical Biology
Thomas Bentsen, Abigail A Kressner, Torsten Dau, Tobias May
Computational speech segregation aims to automatically segregate speech from interfering noise, often by employing ideal binary mask estimation. Several studies have tried to exploit contextual information in speech to improve mask estimation accuracy by using two frequently-used strategies that (1) incorporate delta features and (2) employ support vector machine (SVM) based integration. In this study, two experiments were conducted. In Experiment I, the impact of exploiting spectro-temporal context using these strategies was investigated in stationary and six-talker noise...
January 2018: Journal of the Acoustical Society of America
Maria J Oset-Gasque, Jose Marco-Contelles
Tacrine was the first drug approved by FDA (US) for the treatment of Alzheimer's disease suffering patients. Nowadays, this agent has been withdrawn from the clinics due to secondary effects, among them, and the most important, its hepatotoxicity. However, the research on new tacrine analogues devoid of these therapeutically undesirable effects, but benefiting of their high and well known positive cholinergic power, has produced a number of new non-hepatotoxic tacrines. In this context, in our laboratory, in the last years we have prepared a new heterocyclic tacrines by changing the benzene ring present in tacrine by appropriate heterocyclic motifs...
January 12, 2018: Current Topics in Medicinal Chemistry
Thilo Deckersbach, Amy T Peters, Conor Shea, Aishwarya Gosai, Jonathan P Stange, Andrew D Peckham, Kristen K Ellard, Michael W Otto, Scott L Rauch, Darin D Dougherty, Andrew A Nierenberg
OBJECTIVE: This pilot randomized controlled trial compared Cognitive Behavior Therapy (CBT) and Supportive Psychotherapy (SP) for the treatment of depression in bipolar I disorder. We also examined whether exploratory verbal memory, executive functioning, and neural correlates of verbal memory during functional magnetic resonance imaging (fMRI) predicted change in depression severity. METHODS: Thirty-two adults (ages 18-65) with DSM-IV bipolar I disorder meeting current criteria for a major depressive episode were randomized to 18 weeks of CBT or SP...
December 27, 2017: Journal of Affective Disorders
Serdar Durdagi, Busecan Aksoydan, Ismail Erol, Isik Kantarcioglu, Yavuz Ergun, Gulay Bulut, Melih Acar, Timucin Avsar, George Liapakis, Vlasios Karageorgos, Ramin E Salmas, Barış Sergi, Sara Alkhatib, Gizem Turan, Berfu Nur Yigit, Kutay Cantasir, Bahar Kurt, Turker Kilic
AT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer agents - due to the inhibition of cell proliferation stimulated by A-II. Therefore, AT1 receptors and the A-II biosynthesis mechanisms are targets for the development of new synthetic drugs and therapeutic treatment of various cardiovascular and other diseases...
December 11, 2017: European Journal of Medicinal Chemistry
Bruno Alvarez, Carolina Barra, Morten Nielsen, Massimo Andreatta
Recent advances in proteomics and mass-spectrometry have widely expanded the detectable peptide repertoire presented by major histocompatibility complex (MHC) molecules on the cell surface, collectively known as the immunopeptidome. Finely characterizing the immunopeptidome brings about important basic insights into the mechanisms of antigen presentation, but can also reveal promising targets for vaccine development and cancer immunotherapy. In this report, we describe a number of practical and efficient approaches to analyze immunopeptidomics data, discussing the identification of meaningful sequence motifs in various scenarios and considering current limitations...
January 12, 2018: Proteomics
Chimno Ihuoma Nnadi, Meredith L Jenkins, Daniel R Gentile, Leslie A Bateman, Daniel Zaidman, Trent E Balius, Daniel K Nomura, John E Burke, Kevan M Shokat, Nir London
The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to lack of methodological development. Here, we compared covalent docking to empirical electrophile screening, against the highly dynamic target K-RasG12C. While the overall hit-rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent inhibitor that modifies the inactive, GDP-bound state of K-RasG12C...
January 10, 2018: Journal of Chemical Information and Modeling
Adam Pecina, Jiri Brynda, Lukas Vrzal, Ramachandran Gnanasekaran, Magdalena Horejsi, Saltuk Eyrilmez, Jan Rezac, Martin Lepsik, Pavlina Rezacova, Pavel Hobza, Pavel Majer, Vaclav Veverka, Jindrich Fanfrlik
Accurate prediction of protein-ligand binding affinities is essential for hit-to-lead optimization and virtual screening. The reliability of scoring functions can be improved by implementing of quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function using a challenging set of 10 inhibitors binding to carbonic anhydrase II via Zn2+ in the active site. This new dataset consists of the high-resolution (1.1 - 1.4 Å) crystal structures and experimentally determined Ki values...
January 8, 2018: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
L S Lara, C S Moreira, C M Calvet, G C Lechuga, R S Souza, S C Bourguignon, V F Ferreira, D Rocha, M C S Pereira
The limited efficacy of benznidazole (Bz) indicated by failures of current Phase II clinical trials emphasizes the urgent need to identify new drugs with improved safety and efficacy for treatment of Chagas disease (CD). Herein, we analyzed the efficacy of a series of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against different Trypanosoma cruzi discrete type units (DTUs) of relevant clinical forms of CD. Cytotoxic and trypanocidal effect of naphthoquinone derivatives were assessed in mammalian cells, trypomastigotes and intracellular amastigotes using, luminescent assays (CellTiter-Glo and T...
December 16, 2017: European Journal of Medicinal Chemistry
Virginia C Persinger, Douglas M Whiteside, Lyuba Bobova, Seema D Saigal, Marla J Vannucci, Michael R Basso
OBJECTIVE: Among embedded performance validity tests (PVTs), little research addresses the use of Total Hits and Total False Positives from the California Verbal Learning Test, Second Edition (CVLT-II) in spite of low sensitivity, particularly in psychiatric samples. METHOD: This study examined the classification accuracy of these two measures in individuals with psychiatric disorders or mild traumatic brain injury (MTBI). These samples were separated into two groups using the criteria of passing all PVTs versus failing 2 or more PVTs...
December 28, 2017: Clinical Neuropsychologist
Seema P Deshpande, Michael A Mazzeffi, Erik Strauss, Allison Hollis, Kenichi A Tanaka
Prostacyclin (prostaglandin I2 [PGI2]) is an eicosanoid lipid mediator produced by the endothelial cells. It plays pivotal roles in vascular homeostasis by virtue of its potent vasodilatory and antithrombotic effects. Stable pharmacological analogues of PGI2 are used for treatment of pulmonary hypertension and right ventricular failure. PGI2 dose dependently inhibits platelet activation induced by adenosine-5'-diphosphate, arachidonic acid, collagen, and low-dose thrombin. This property has led to its use as an alternative to direct thrombin inhibitors in patients with type II heparin-induced thrombocytopenia (HIT) undergoing cardiac surgery...
December 1, 2017: Seminars in Cardiothoracic and Vascular Anesthesia
Timo Brandenburger, Thomas Dimski, Torsten Slowinski, Detlef Kindgen-Milles
Today, up to 20% of all intensive care unit patients require renal replacement therapy (RRT), and continuous renal replacement therapies (CRRT) are the preferred technique. In CRRT, effective anticoagulation of the extracorporeal circuit is mandatory to prevent clotting of the circuit or filter and to maintain filter performance. At present, a variety of systemic and regional anticoagulation modes for CRRT are available. Worldwide, unfractionated heparin is the most widely used anticoagulant. All systemic techniques are associated with significant adverse effects...
September 2017: Best Practice & Research. Clinical Anaesthesiology
L K Schoch, A Asiama, M Zahurak, S Shanbhag, J Hurtt, K Sawyer, L J Swinnen, N Wagner-Johnston, R J Jones, R F Ambinder, Douglas E Gladstone
BACKGROUND: Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients. PATIENTS/METHODS: After HDC, everolimus was dosed to serum trough levels (goal 3-15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non-hematologic and < grade III hematologic toxicities...
December 13, 2017: Cancer Chemotherapy and Pharmacology
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