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Small molecule structure

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https://www.readbyqxmd.com/read/29782488/insight-into-small-molecule-binding-to-the-neonatal-fc-receptor-by-x-ray-crystallography-and-100-khz-magic-angle-spinning-nmr
#1
Daniel Stöppler, Alex Macpherson, Susanne Smith-Penzel, Nicolas Basse, Fabien Lecomte, Hervé Deboves, Richard D Taylor, Tim Norman, John Porter, Lorna C Waters, Marta Westwood, Ben Cossins, Katharine Cain, James White, Robert Griffin, Christine Prosser, Sebastian Kelm, Amy H Sullivan, David Fox, Mark D Carr, Alistair Henry, Richard Taylor, Beat H Meier, Hartmut Oschkinat, Alastair D Lawson
Aiming at the design of an allosteric modulator of the neonatal Fc receptor (FcRn)-Immunoglobulin G (IgG) interaction, we developed a new methodology including NMR fragment screening, X-ray crystallography, and magic-angle-spinning (MAS) NMR at 100 kHz after sedimentation, exploiting very fast spinning of the nondeuterated soluble 42 kDa receptor construct to obtain resolved proton-detected 2D and 3D NMR spectra. FcRn plays a crucial role in regulation of IgG and serum albumin catabolism. It is a clinically validated drug target for the treatment of autoimmune diseases caused by pathogenic antibodies via the inhibition of its interaction with IgG...
May 21, 2018: PLoS Biology
https://www.readbyqxmd.com/read/29781349/recent-advances-in-targeting-protein-arginine-methyltransferase-enzymes-in-cancer-therapy
#2
Emily Smith, Wei Zhou, Polina Shindiapina, Said Sif, Chenglong Li, Robert A Baiocchi
Exploration in the field of epigenetics has revealed the diverse roles of the protein arginine methyltransferase (PRMT) family of proteins in multiple disease states. These findings have led to the development of specific inhibitors and discovery of several new classes of drugs with potential to treat both benign and malignant conditions. Areas covered: We provide an overview on the role of PRMT enzymes in healthy and malignant cells, highlighting the role of arginine methylation in specific pathways relevant to cancer pathogenesis...
May 21, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29781252/subtype-selective-inhibition-of-acid-sensing-ion-channel-3-by-a-natural-flavonoid
#3
Xiao-Gang Yan, Wei-Guang Li, Xin Qi, Jia-Jie Zhu, Chen Huang, Shao-Ling Han, Qin Jiang, Tian-Le Xu, Jian-Hua Liu
AIMS: Acid-sensing ion channels (ASICs) are extracellular proton-gated cation channels that have been implicated in multiple physiological and pathological processes, and peripheral ASIC3 prominently participate into the pathogenesis of chronic pain, itch, and neuroinflammation, which necessitates the need for discovery and development of novel modulators in a subtype-specific manner. METHODS: Whole-cell patch clamp recordings and behavioral assays were used to examine the effect of several natural compounds on the ASIC-mediated currents and acid-induced nocifensive behavior, respectively...
May 20, 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29780480/on-chip-measurements-of-protein-unfolding-from-direct-observations-of-micron-scale-diffusion
#4
Yuewen Zhang, Emma V Yates, Liu Hong, Kadi L Saar, Georg Meisl, Christopher M Dobson, Tuomas P J Knowles
Investigations of protein folding, unfolding and stability are critical for the understanding of the molecular basis of biological structure and function. We describe here a microfluidic approach to probe the unfolding of unlabelled protein molecules in microliter volumes. We achieve this objective through the use of a microfluidic platform, which allows the changes in molecular diffusivity upon folding and unfolding to be detected directly. We illustrate this approach by monitoring the unfolding of bovine serum albumin in solution as a function of pH...
April 14, 2018: Chemical Science
https://www.readbyqxmd.com/read/29780475/development-of-microfluidic-platforms-for-the-synthesis-of-metal-complexes-and-evaluation-of-their-dna-affinity-using-online-fret-melting-assays
#5
Viktoria Rakers, Paolo Cadinu, Joshua B Edel, Ramon Vilar
Guanine-rich DNA sequences can fold into quadruple-stranded structures known as G-quadruplexes. These structures have been proposed to play important biological roles and have been identified as potential drug targets. As a result, there is increasing interest in developing small molecules that can bind to G-quadruplexes. So far, these efforts have been mostly limited to conventional batch synthesis. Furthermore, no quick on-line method to assess new G-quadruplex binders has been developed. Herein, we report on two new microfluidic platforms to: (a) readily prepare G-quadruplex binders (based on metal complexes) in flow, quantitatively and without the need for purification before testing; (b) a microfluidic platform (based on FRET melting assays of DNA) that enables the real-time and on-line assessment of G-quadruplex binders in continuous flow...
April 14, 2018: Chemical Science
https://www.readbyqxmd.com/read/29779955/linking-genomic-and-metabolomic-natural-variation-uncovers-nematode-pheromone-biosynthesis
#6
Jan M Falcke, Neelanjan Bose, Alexander B Artyukhin, Christian Rödelsperger, Gabriel V Markov, Joshua J Yim, Dominik Grimm, Marc H Claassen, Oishika Panda, Joshua A Baccile, Ying K Zhang, Henry H Le, Dino Jolic, Frank C Schroeder, Ralf J Sommer
In the nematodes Caenorhabditis elegans and Pristionchus pacificus, a modular library of small molecules control behavior, lifespan, and development. However, little is known about the final steps of their biosynthesis, in which diverse building blocks from primary metabolism are attached to glycosides of the dideoxysugar ascarylose, the ascarosides. We combine metabolomic analysis of natural isolates of P. pacificus with genome-wide association mapping to identify a putative carboxylesterase, Ppa-uar-1, that is required for attachment of a pyrimidine-derived moiety in the biosynthesis of ubas#1, a major dauer pheromone component...
May 14, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29779706/plant-water-transport-and-aquaporins-in-oxygen-deprived-environments
#7
Xiangfeng Tan, Hao Xu, Shanjida Khan, Maria A Equiza, Seong H Lee, Maryamsadat Vaziriyeganeh, Janusz J Zwiazek
Oxygen deprivation commonly affects plants exposed to flooding and soil compaction. The resulting root hypoxia has an immediate effect on plant water relations and upsets water balance. Hypoxia inhibits root water transport and triggers stomatal closure. The processes contributing to the inhibition of root hydraulic conductivity and conductance (hydraulic conductivity of the whole root system) are complex and involve changes in root morphology and the functions of aquaporins. Aquaporins (AQPs) comprise a group of membrane intrinsic proteins that are responsible for the transport of water, as well as some small neutral solutes and ions...
May 12, 2018: Journal of Plant Physiology
https://www.readbyqxmd.com/read/29778645/screening-and-selection-of-artificial-riboswitches
#8
Svetlana V Harbaugh, Jennifer Martin, Jenna Weinstein, Grant Ingram, Nancy Kelley-Loughnane
Synthetic riboswitches are engineered to regulate gene expression in response to a variety of non-endogenous small molecules, and a challenge to select this engineered response requires robust screening tools. A new synthetic riboswitch can be created by linking an in vitro-selected aptamer library with a randomized expression platform followed by in vivo selection and screening. In order to determine response to analyte, we developed a dual-color reporter comprising elements of the E. coli fimbriae phase variation system: recombinase FimE controlled by a synthetic riboswitch and an invertible DNA segment (fimS) containing a constitutively active promoter placed between two fluorescent protein genes...
May 17, 2018: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/29775968/in-silico-structure-prediction-and-inhibition-mechanism-studies-of-athda14-as-revealed-by-homology-modeling-docking-molecular-dynamics-simulation
#9
Ming-Lang Zhao, Wang Wang, Hu Nie, Sha-Sha Cao, Lin-Fang Du
Histone deacetylases (HDACs) play a significant role in the epigenetic mechanism by catalyzing deacetylation of lysine on histone in both animals and plants. HDACs involved in growth, development and response to stresses in plants. Arabidopsis thaliana histone deacetylase 14 (AtHDA14) is found to localize in the mitochondria and chloroplasts, and it involved in photosynthesis and melatonin biosynthesis. However, its mechanism of action was still unknowns so far. Therefore, in this study, we constructed AtHDA14 protein model using homology modeling method, validated using PROCHECK and presented using Ramachandran plots...
May 6, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29775584/conformational-activation-of-argonaute-by-distinct-yet-coordinated-actions-of-the-hsp70-and-hsp90-chaperone-systems
#10
Kotaro Tsuboyama, Hisashi Tadakuma, Yukihide Tomari
Loading of small RNAs into Argonaute, the core protein in RNA silencing, requires the Hsp70/Hsp90 chaperone machinery. This machinery also activates many other clients, including steroid hormone receptors and kinases, but how their structures change during chaperone-dependent activation remains unclear. Here, we utilized single-molecule Förster resonance energy transfer (smFRET) to probe the conformational changes of Drosophila Ago2 mediated by the chaperone machinery. We found that empty Ago2 exists in various closed conformations...
May 17, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29774900/multiplex-detection-of-quality-indicator-molecule-targets-in-urine-using-programmable-hairpin-probes-based-on-a-simple-double-t-type-microchip-electrophoresis-platform-and-isothermal-polymerase-catalyzed-target-recycling
#11
Lingying Zhou, Ning Gan, Yongxiang Wu, Futao Hu, Jianyuan Lin, Yuting Cao, Dazhen Wu
Recently, it has been crucial to be able to detect and quantify small molecular targets simultaneously in biological samples. Herein, a simple and conventional double-T type microchip electrophoresis (MCE) based platform for the multiplex detection of quality indicator molecule targets in urine, using ampicillin (AMPI), adenosine triphosphate (ATP) and estradiol (E2) as models, was developed. Several programmable hairpin probes (PHPs) were designed for detecting different targets and triggering isothermal polymerase-catalyzed target recycling (IPCTR) for signal amplification...
May 18, 2018: Analyst
https://www.readbyqxmd.com/read/29773682/water-structure-changes-in-oxime-mediated-reactivation-process-of-phosphorylated-human-acetylcholinesterase
#12
Irina V Zueva, Sofya V Lushchekina, Patrick Masson
The role of water in oxime-mediated reactivation of phosphylated cholinesterases has been asked with recurrence. To investigate oximate water structure changes in this reaction, reactivation of paraoxon-inhibited human acetylcholinesterase (AChE) was performed by the oxime HI-6 at different pH in the presence and absence of lyotropic salts: a neutral salt (NaCl), a strong chaotropic salt (LiSCN) and strong kosmotropic salts (ammonium sulfate and phosphate HPO4 2- ). At the same time, molecular dynamic simulations of enzyme reactivation under the same conditions were performed over 100 ns...
May 17, 2018: Bioscience Reports
https://www.readbyqxmd.com/read/29773370/rheological-and-structural-properties-of-complex-arabinoxylans-from-plantago-ovata-seed-mucilage-under-non-gelled-conditions
#13
Long Yu, Gleb E Yakubov, Marta Martínez-Sanz, Elliot P Gilbert, Jason R Stokes
Two gel-forming arabinoxylan (AX) fractions with very similar linkage composition and molecular weight distributions have been isolated from Plantago ovata seed mucilage. Both isolated fractions have distinct gel properties attributed to differences in intermolecular hydrogen bonding. This study probes the effect of hydrogen bonding on molecular interactions of P. ovata AX fractions under non-gelled conditions achieved using a mild hydrogen bonding inhibitor, 0.2 M KOH. Chain conformation, relaxation dynamics and interactions between AX molecules are investigated using a combination of rheological techniques and small angle X-ray and neutron scattering...
August 1, 2018: Carbohydrate Polymers
https://www.readbyqxmd.com/read/29771936/assigning-crystallographic-electron-densities-with-free-energy-calculations-the-case-of-the-fluoride-channel-fluc
#14
Igor Ariz-Extreme, Jochen S Hub
Approximately 90% of the structures in the Protein Data Bank (PDB) were obtained by X-ray crystallography or electron microscopy. Whereas the overall quality of structure is considered high, thanks to a wide range of tools for structure validation, uncertainties may arise from density maps of small molecules, such as organic ligands, ions or water, which are non-covalently bound to the biomolecules. Even with some experience and chemical intuition, the assignment of such disconnected electron densities is often far from obvious...
2018: PloS One
https://www.readbyqxmd.com/read/29771457/transition-metal-ions-mediated-tyrosine-based-short-peptide-amphiphile-nanostructures-inhibit-bacterial-growth
#15
Khashti Ballabh Joshi, Ramesh Singh, Narendra Kumar Mishra, Vikas Kumar, Vandana Vinayak
We report the design and synthesis of biocompatible small peptide based molecule for the controlled and targeted delivery of the encapsulated bioactive metal ions via transforming their internal nanostructures. Tyrosine based short peptide amphiphile (sPA) was synthesized which self-assembled into β-sheet like secondary structures. The self assembly of the designed sPA was modulated by using different bioactive transition metal ions which is confirmed by spectroscopic and microscopic techniques. These bioactive metal ions conjugated sPA hybrid structures are further used to develop antibacterial materials...
May 17, 2018: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29771107/design-and-synthesis-of-a-biocompatible-1d-coordination-polymer-as-anti-breast-cancer-drug-carrier-5-fu-in-vitro-and-in-vivo-studies
#16
Mahsa Rezaei, Alireza Abbasi, Rassoul Dinarvand, Mahmood Jeddi-Tehrani, Jan Janczak
Designable coordination polymers with suitable chemical diversities and biocompatible structures have been proposed as a promising class of vehicles for drug delivery systems. Here, we hydrothermally synthesized a novel one-dimensional (1D) coordination polymer, [Zn(H2 O)6 K2 (H2 BTC)2 (H2 O)4 ](H2 BTC)2 ·2H2 O, where H3 BTC = benzene-1,3,5-tricarboxylic acid (trimesic acid), cp.1. As the hydrogen bonds stabilized 1D chains in three dimensions, the cp.1 could be a good candidate for delivering small-molecule chemotherapeutics such as 5-fluorouracil (5-Fu)...
May 17, 2018: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29770817/the-dietary-compound-luteolin-inhibits-pancreatic-cancer-growth-by-targeting-bcl-2
#17
Zhimei Li, Yiyuan Zhang, Lixia Chen, Hua Li
Overexpression of the prosurvival protein BCL-2 contributes to malignant cell initiation, progression and resistance to treatment. Agents that function as its natural antagonists targeting BCL-2 must provide therapeutic benefit. In SW1990 pancreatic cancer cells, amplified BCL-2 was observed, which was believed to offer advantages for malignant cell survival and lead to poor patient outcome. Using structure-based virtual ligand screening, luteolin was found to be a natural small-molecule inhibitor of BCL-2, which exhibited dose-response proapoptosis activity in a BCL-2 dependent manner in vitro...
May 17, 2018: Food & Function
https://www.readbyqxmd.com/read/29770599/structural-analysis-of-small-molecule-binding-to-the-baz2a-and-baz2b-bromodomains
#18
Andrea Dalle Vedove, Dimitrios Spiliotopoulos, Vito Giuseppe D'Agostino, Jean-Rémy Marchand, Andrea Unzue, Cristina Nevado, Graziano Lolli, Amedeo Caflisch
The bromodomain-containing protein BAZ2A is a validated target in prostate cancer, while the function of its paralog BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a very similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand makes essentially identical interactions in the BAZ2A and BAZ2B bromodomains...
May 17, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29769520/hollow-organic-capsules-assemble-into-cellular-semiconductors
#19
Boyuan Zhang, Raúl Hernández Sánchez, Yu Zhong, Melissa Ball, Maxwell W Terban, Daniel Paley, Simon J L Billinge, Fay Ng, Michael L Steigerwald, Colin Nuckolls
Self-assembly of electroactive molecules is a promising route to new types of functional semiconductors. Here we report a capsule-shaped molecule that assembles itself into a cellular semiconducting material. The interior space of the capsule with a volume of ~415 Å3 is a nanoenvironment that can accommodate a guest. To self-assemble these capsules into electronic materials, we functionalize the thiophene rings with bromines, which encode self-assembly into two-dimensional layers held together through halogen bonding interactions...
May 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29769246/small-molecule-positive-allosteric-modulators-of-the-%C3%AE-2-adrenoceptor-isolated-from-dna-encoded-libraries
#20
Seungkirl Ahn, Biswaranjan Pani, Alem W Kahsai, Eva K Olsen, Gitte Husemoen, Mikkel Vestrgaard, Lei Jin, Shuai Zhao, Laura M Wingler, Paula K Rambarat, Rishabh K Simhal, Thomas T Xu, Lillian D Sun, Paul J Shim, Dean P Staus, Li-Yin Huang, Thomas Franch, Xin Chen, Robert J Lefkowitz
Conventional drug discovery efforts at the β2 -adrenoceptor (β2 AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein-coupled receptors (GPCRs) with DNA-encoded small molecule libraries, we have discovered and characterized the first β2 AR small molecule positive allosteric modulators (PAMs) - compound-6 [(R)-N-(4-amino-1-(4-(tert-butyl)phenyl)-4-oxobutan-2-yl)-5-(N-isopropyl-N-methylsulfamoyl)-2-((4-methoxyphenyl) thio)benzamide] and its analogs...
May 16, 2018: Molecular Pharmacology
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