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https://www.readbyqxmd.com/read/28646631/synthesis-of-novel-and-functionally-selective-non-competitive-muscarinic-antagonists-as-chemical-probes
#1
John F Boulos, Jan Jakubik, John M Boulos, Jelena Momirov, Alena Randakova
Muscarinic receptors are known to play important biological roles and are drug targets for several human diseases. In a pilot study, novel muscarinic antagonists were synthesized and used as chemical probes to obtain additional information of the muscarinic pharmacophore. The design of these ligands made use of current orthosteric and allosteric models of drug-receptor interactions together with chemical motifs known to achieve muscarinic receptor selectivity. This approach has led to the discovery of several non-competitive muscarinic ligands that strongly bind at a secondary receptor site...
June 24, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28646511/control-of-autoimmune-inflammation-using-liposomes-to-deliver-positive-allosteric-modulators-of-metabotropic-glutamate-receptors
#2
Joshua M Gammon, Arjun R Adapa, Christopher M Jewell
Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator of metabotropic glutamate receptor 4 (mGluR4), can promote regulatory T cells by altering cytokine secretion to bias T cell differentiation...
June 24, 2017: Journal of Biomedical Materials Research. Part A
https://www.readbyqxmd.com/read/28644875/estimation-of-the-optimal-dosing-regimen-of-escitalopram-in-dogs-a-dose-occupancy-study-with-11c-dasb
#3
Olivia Taylor, Nick Van Laeken, Ingeborgh Polis, Robrecht Dockx, Lise Vlerick, Andre Dobbeleir, Ingeborg Goethals, Jimmy Saunders, Nele Sadones, Chris Baeken, Filip De Vos, Kathelijne Peremans
Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0...
2017: PloS One
https://www.readbyqxmd.com/read/28643003/recent-developments-in-solution-nuclear-magnetic-resonance-nmr-based-molecular-biology
#4
REVIEW
Joshua J Ziarek, Diego Baptista, Gerhard Wagner
Visualizing post-translational modifications, conformations, and interaction surfaces of protein structures at atomic resolution underpins the development of novel therapeutics to combat disease. As computational resources expand, in silico calculations coupled with experimentally derived structures and functional assays have led to an explosion in structure-based drug design (SBDD) with several compounds in clinical trials. It is increasingly clear that "hidden" transition-state structures along activation trajectories can be harnessed to develop novel classes of allosteric inhibitors...
June 23, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28642545/high-throughput-screening-of-small-molecule-inhibitors-of-the-streptococcus-quorum-sensing-signal-pathway
#5
Seiji Ishii, Kenji Fukui, Satoshi Yokoshima, Kazuo Kumagai, Youko Beniyama, Tetsuya Kodama, Tohru Fukuyama, Takayoshi Okabe, Tetsuo Nagano, Hirotatsu Kojima, Takato Yano
The main components of the quorum-sensing system are expected to be favorable targets for drug development to combat various chronic infectious diseases. ComA of Streptococcus is an ATP-binding cassette transporter containing a peptidase domain (PEP), which is essential for the quorum-sensing signal production. Using high-throughput screening, we found a potent small molecule that suppressed the S. mutans quorum-sensing pathway through inhibition of PEP activity. The compound effectively attenuated the biofilm formation and competence development of S...
June 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28642370/in-vitro-cytochrome-p450-46a1-cyp46a1-activation-by-neuroactive-compounds
#6
Natalia Mast, Kyle W Anderson, Kevin M Johnson, Thanh T N Phan, F Peter Guengerich, Irina A Pikuleva
Cytochrome P450 46A1 (CYP46A1, cholesterol 24-hydroxylase) is the enzyme responsible for the majority of cholesterol elimination from the brain. Previously, we found that the anti-HIV drug efavirenz (EFV) can pharmacologically activate CYP46A1 in mice. Herein, we investigated whether CYP46A1 could also be activated by endogenous compounds, including major neurotransmitters. In vitro experiments with purified recombinant CYP46A1 indicated that CYP46A1 is activated by L-glutamate (L-Glu), L-aspartate, γ-aminobutyric acid, and acetylcholine, with L-Glu eliciting the highest increase (3-fold) in CYP46A1-mediated cholesterol 24-hydroxylation...
June 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28642232/a-single-amino-acid-residue-at-transmembrane-domain-4-of-the-alpha-subunit-influences-carisoprodol-direct-gating-efficacy-at-gabaa-receptors
#7
Manoj Kumar, Manish Kumar, John Freund, Glenn H Dillon
The muscle relaxant carisoprodol (CSP, trade name Soma) has recently been controlled at the federal level as a Schedule IV drug due to its high abuse potential and consequences of misuse, such as withdrawal syndrome, delusions, seizures and even death. Recent work has shown that carisoprodol can directly gate and allosterically modulate the GABAA receptor. These actions are subunit-dependent; compared to other GABAA receptors, carisoprodol has nominal direct gating effects in α3β2γ2receptors. Here, using site-directed-mutagenesis and whole cell patch clamp electrophysiology in transiently transfected HEK293 cells, we examined the role of GABAA receptor α subunit transmembrane domain 4 (TM4) amino acids in direct gating and allosteric modulatory actions of carisoprodol...
June 22, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28640864/targeting-breast-cancer-cells-by-mrs1477-a-positive-allosteric-modulator-of-trpv1-channels
#8
Mustafa Nazıroğlu, Bilal Çiğ, Walter Blum, Csaba Vizler, Andrea Buhala, Annamária Marton, Róbert Katona, Katalin Jósvay, Beat Schwaller, Zoltán Oláh, László Pecze
There is convincing epidemiological and experimental evidence that capsaicin, a potent natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist, has anticancer activity. However, capsaicin cannot be given systemically in large doses, because of its induction of acute pain and neurological inflammation. MRS1477, a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477 evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial cells...
2017: PloS One
https://www.readbyqxmd.com/read/28640851/ligand-mediated-and-tertiary-interactions-cooperatively-stabilize-the-p1-region-in-the-guanine-sensing-riboswitch
#9
Christian A Hanke, Holger Gohlke
Riboswitches are genetic regulatory elements that control gene expression depending on ligand binding. The guanine-sensing riboswitch (Gsw) binds ligands at a three-way junction formed by paired regions P1, P2, and P3. Loops L2 and L3 cap the P2 and P3 helices and form tertiary interactions. Part of P1 belongs to the switching sequence dictating the fate of the mRNA. Previous studies revealed an intricate relationship between ligand binding and presence of the tertiary interactions, and between ligand binding and influence on the P1 region...
2017: PloS One
https://www.readbyqxmd.com/read/28639411/mapping-the-allosteric-sites-of-the-a2a-adenosine-receptor
#10
Alisha D Caliman, Yinglong Miao, J Andrew McCammon
The A2A adenosine receptor (A2A AR) is a G protein-coupled receptor that is pharmacologically targeted for the treatment of inflammation, sepsis, cancer, neuro-degeneration, and Parkinson's disease. Recently, we applied long-timescale molecular dynamics simulations on two ligand-free receptor conformations, starting from the agonist-bound (PDB ID:3QAK) and antagonist-bound (PDB ID:3EML) X-ray structures. This analysis revealed four distinct conformers of the A2A AR: the active, intermediate 1, intermediate 2, and inactive...
June 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28639360/the-mechanism-of-coupling-between-oxido-reduction-and-proton-translocation-in-respiratory-chain-enzymes
#11
Sergio Papa, Giuseppe Capitanio, Francesco Papa
The respiratory chain of mitochondria and bacteria is made up of a set of membrane-associated enzyme complexes which catalyse sequential, stepwise transfer of reducing equivalents from substrates to oxygen and convert redox energy into a transmembrane protonmotive force (PMF) by proton translocation from a negative (N) to a positive (P) aqueous phase separated by the coupling membrane. There are three basic mechanisms by which a membrane-associated redox enzyme can generate a PMF. These are membrane anisotropic arrangement of the primary redox catalysis with: (i) vectorial electron transfer by redox metal centres from the P to the N side of the membrane; (ii) hydrogen transfer by movement of quinones across the membrane, from a reduction site at the N side to an oxidation site at the P side; (iii) a different type of mechanism based on co-operative allosteric linkage between electron transfer at the metal redox centres and transmembrane electrogenic proton translocation by apoproteins...
June 21, 2017: Biological Reviews of the Cambridge Philosophical Society
https://www.readbyqxmd.com/read/28637198/multi-target-activity-of-hemidesmus-indicus-decoction-against-innovative-hiv-1-drug-targets-and-characterization-of-lupeol-mode-of-action
#12
Francesca Esposito, Manuela Mandrone, Claudia Del Vecchio, Ilaria Carli, Simona Distinto, Angela Corona, Mariacaterina Lianza, Dario Piano, Massimo Tacchini, Elias Maccioni, Filippo Cottiglia, Elisa Saccon, Ferruccio Poli, Cristina Parolin, Enzo Tramontano
Despite the availability of several anti-retrovirals there is still an urgent need for developing novel therapeutic strategies and finding new drugs against underexplored HIV-1 targets. Among them, there are the HIV-1 Reverse Transcriptase (RT)-associated Ribonuclease H (RNase H) function and the cellular α-glucosidase, involved in the control mechanisms of N-linked glycoproteins formation in the endoplasmic reticulum. It is known that many natural compounds, such as pentacyclic triterpenes, are a promising class of HIV-1 inhibitors...
June 20, 2017: Pathogens and Disease
https://www.readbyqxmd.com/read/28636915/probing-the-structural-dynamics-of-the-nmda-receptor-activation-by-coarse-grained-modeling
#13
Wenjun Zheng, Han Wen, Gary J Iacobucci, Gabriela K Popescu
N-Methyl-D-aspartate (NMDA) receptors are glutamate-gated excitatory channels that play essential roles in brain functions. High-resolution structures have been solved for an allosterically inhibited and agonist-bound form of a functional NMDA receptor; however, other key functional states (particularly the active open-channel state) were only resolved at moderate resolutions by cryo-electron microscopy (cryo-EM). To decrypt the mechanism of the NMDA receptor activation, structural modeling is essential to provide presently missing information about structural dynamics...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28636914/peptide-protein-binding-investigated-by-far-ir-spectroscopy-and-molecular-dynamics-simulations
#14
Yoann Cote, Yves Nominé, Juan Ramirez, Petra Hellwig, Roland H Stote
Molecular dynamics (MD) simulations and far-infrared (far-IR) spectroscopy were combined to study peptide binding by the second PDZ domain (PDZ1) of MAGI1, which has been identified as an important target for the Human Papilloma Virus. PDZ1 recognizes and binds to the C-terminal end of the E6 protein from high-risk Human Papilloma Virus. The far-IR spectra of two forms of the protein, an unbound APO form and a HOLO form (where the PDZ1 is bound to an 11-residue peptide derived from the C terminus of HPV16 E6), were obtained...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28634302/structure-of-human-fe-s-assembly-subcomplex-reveals-unexpected-cysteine-desulfurase-architecture-and-acyl-acp-isd11-interactions
#15
Seth A Cory, Jonathan G Van Vranken, Edward J Brignole, Shachin Patra, Dennis R Winge, Catherine L Drennan, Jared Rutter, David P Barondeau
In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP). This NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters. Here we present crystallographic and electron microscopic structures of the SDA complex coupled to enzyme kinetic and cell-based studies to provide structure-function properties of a mitochondrial cysteine desulfurase...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28634294/hidden-electrostatic-basis-of-dynamic-allostery-in-a-pdz-domain
#16
Amit Kumawat, Suman Chakrabarty
Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28634233/structural-analyses-of-human-thymidylate-synthase-reveal-a-site-that-may-control-conformational-switching-between-active-and-inactive-states
#17
Dan Chen, Anna Jansson, Daniel Sim, Andreas Larsson, Pär Nordlund
Thymidylate synthase (TS) is the sole enzyme responsible for de novo biosynthesis of thymidylate (TMP) and is essential for cell proliferation and survival. Inhibition of human TS (hTS) has been extensively investigated for cancer chemotherapy, but several aspects of its activity and regulation are still uncertain. In this study, we performed comprehensive structural and biophysical studies of hTS using crystallography and thermal shift assay and provided the first detailed structural information on the conformational changes induced by ligand binding to the hTS active site...
June 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28634232/the-phosphocarrier-protein-hpr-of-the-bacterial-phosphotransferase-system-globally-regulates-energy-metabolism-by-directly-interacting-with-multiple-enzymes-in-escherichia-coli
#18
Irina A Rodionova, Zhongge Zhang, Jitender Mehla, Norman Goodacre, Mohan Babu, Andrew Emili, Peter Uetz, Milton H Saier
The histidine-phosphorylatable phosphocarrier protein HPr, is an essential component of the sugar-transporting phosphotransferase system (PTS) in many bacteria. Recent interactome findings suggested that HPr interacts with several carbohydrate-metabolizing enzymes, but whether HPr plays a regulatory role was unclear. Here, we provide evidence that HPr interacts with a large number of proteins in Escherichia coli. We demonstrate HPr-dependent allosteric regulation of the activities of pyruvate kinase (PykF, but not PykA), phosphofructokinase (PfkB, but not PfkA), glucosamine 6-phosphate deaminase (NagB) and adenylate kinase (Adk)...
June 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28633899/discovery-of-bms-961955-an-allosteric-inhibitor-of-the-hepatitis-c-virus-ns5b-polymerase
#19
Barbara Zhizhen Zheng, Stanley V D'Andrea, Umesh Hanumegowda, Jay O Knipe, Kathy Mosure, Xiaoliang Zhuo, Julie A Lemm, Mengping Liu, Karen L Rigat, Ying-Kai Wang, Hua Fang, Chris Poronsky, Jingfang Cutrone, Dauh-Rurng Wu, Pirama Nayagam Arunachalam, T J Balapragalathan, Arunachalam Arumugam, Arvind Mathur, Nicholas A Meanwell, Min Gao, Susan B Roberts, John F Kadow
The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as Ximency(TM).
June 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28631100/co-modulation-of-an-allosteric-modulator-of-nicotinic-receptor-cholinesterase-inhibitor-galantamine-and-a-5-ht4-receptor-agonist-rs-67333-effect-on-scopolamine-induced-memory-deficit-in-the-mouse
#20
Thomas Freret, Véronique Lelong-Boulouard, Pierre Lecouflet, Katia Hamidouche, François Dauphin, Michel Boulouard
AIM: It is widely assumed that the upcoming therapeutics for Alzheimer's disease will require to act on more than one target to be effective. We investigated here whether a combination of the nicotinic receptor allosteric modulator/cholinesterase inhibitor galantamine can act synergistically with the type 4 serotonin receptor (5-HT4R) partial agonist, RS-67333, to counterbalance deficits in short- and long-term memory. To select sub-efficacious doses of both drugs, dose-response studies were first performed on the scopolamine-induced deficits of spontaneous alternation in the Y-maze task and of acquisition and retrieval processes in a passive avoidance task...
June 19, 2017: Psychopharmacology
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