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Ligand Design

Zhennan Zhao, Xiang Zhang, Chang-E Li, Tianfeng Chen
The effective design of a targeted drug delivery system could improve the therapeutic efficacy of anticancer drugs by reducing their undesirable adsorption and toxic side effects. Here, an RGD-peptide functionalized and bioresponsive ruthenium prodrug (Ru-RGD) was designed for both cancer therapy and clinical diagnosis. This prodrug can be selectively delivered to cervical tumor sites to enhance theranostic efficacy. The benzimidazole-based ligand of the complex is susceptible to acidic conditions so, after reaching the tumor microenvironment, ligand substitution occurs and the therapeutic drug is released...
December 5, 2018: Biomaterials
Nai She, Yuan Zhao, Jingjing Hao, Songqiang Xie, Chaojie Wang
O-linked N-acetylglucosamine transferase (OGT) is an essential enzyme that catalyzes the covalent bonding of N-acetylglucosamine (GlcNAc) to the hydroxyl group of a serine or threonine in the target protein. It plays an important role in many important cellular physiological catalytic reactions. Here, we determine the binding mode and the binding free energy of the OGT product (uridine diphosphate, UDP) as well as the hydrogen-bond-dependent release mechanism using extensive molecular dynamic simulations. The Lys634, Asn838, Gln839, Lys842, His901, and Asp925 residues were identified to play a major role in the UDP stabilization in the active site of OGT, where hydrogen bonding and π-π interactions mainly occur...
December 11, 2018: Biochimica et biophysica acta. General subjects
Lars Edvinsson
Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (CLR + RAMP1) offer considerable improvements over existing drugs in migraine prophylaxis and are the first designed to act on the trigeminal pain system. Erenumab is approved by the FDA and EMA and has reached the market since May 2018. Two antibodies, fremanezumab and galcanezumab, directed towards the CGRP ligand, were approved by the FDA in September 2018. To view this Bench to Bedside, open or download the PDF.
December 13, 2018: Cell
Fabrice Pointillart, Jiang-Kun Ou-Yang, Guglielmo Fernandez Garcia, Vincent Montigaud, Jessica Flores Gonzalez, Rémi Marchal, Ludovic Favereau, Federico Totti, Jeanne Crassous, Olivier Cador, Lahcène Ouahab, Boris Le Guennic
The design of a coordination complex that involves a ligand combining both a tetrathiafulvalene core and a helicene fragment was achieved thanks to the reaction between the new 2-{1-[2-methyl[6]helicene]-4,5-[4,5-bis(propylthio)tetrathiafulvalenyl]-1 H-benzimidazol-2-yl}pyridine ligand (L) and the Dy(hfac)3 ·2H2 O metalloprecursor. Magnetic investigations showed field-induced single-molecule-magnet (SMM) behavior under an applied magnetic field of 1000 Oe for [Dy(hfac)3 (L)]·0.5CH2 Cl2 , while experimentally oriented single-crystal magnetic measurements allowed for determination of the magnetic anisotropy orientation...
December 14, 2018: Inorganic Chemistry
Mingxia Lu, Yee Yee Khine, Fan Chen, Cheng Cao, Christopher J Garvey, Hongxu Lu, Martina H Stenzel
Glycopolymer-coated nanoparticles have attracted significant interest over the past few years, because of their selective interaction with carbohydrate receptors found on the surface of cells. While the type of carbohydrate determines the strength of the ligand-receptor interaction, the presentation of the sugar can be highly influential as the carbohydrate needs to be accessible in order to display good binding. To shine more light on the relationship between nanoparticle structure and cell uptake, we have designed several micelles based on fructose containing block copolymers, which are selective to GLUT5 receptors found on breast cancer cell lines...
December 14, 2018: Biomacromolecules
Ghazaleh Darmani, Til O Bergmann, Carl Zipser, David Baur, Florian Müller-Dahlhaus, Ulf Ziemann
Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS-evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage-gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double-blinded randomized placebo-controlled crossover design...
December 13, 2018: Human Brain Mapping
Kaixun Cui, Wanfu Zhong, Lingyun Li, Zanyong Zhuang, Liuyi Li, Jinhong Bi, Yan Yu
Yolk-shell nanoreactors have received considerable interest for use in catalysis. However, the controlled synthesis of continuous crystalline shells without imperfections or cracks remains challenging. Here, a strategy for the synthesis of yolk-shell metal nanoparticles@covalent organic framework (MNPs@COF) nanoreactors by using MNPs@ZIF-8 core-shell nanostructures as a self-template is designed and developed. The COF shell is formed through an amorphous-to-crystalline transformation process of a polyimine shell in a mildly acidic solution, while the ZIF-8 is etched in situ, generating a void space between the MNPs core and the COF shell...
December 13, 2018: Small
Sara Redenti, Irene Marcovih, Teresa De Vita, Conception Perez, Rita De Zorzi, Nicola Demitri, Daniel I Perez, Giovanni Bottegoni, Paola Bisignano, Maicol Bissaro, Stefano Moro, Ana Martinez, Paola Storici, Giampiero Spalluto, Andrea Cavalli, Stephanie Federico
GSK-3β and CK-1δ are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking-based design.. Compound 12, 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed a combined inhibitory activity against GSK-3β and CK-1δ [IC50(GSK-3β)= 0.17 μM; IC50(CK-1δ)= 0.68 μM]. In particular, a classical ATP competition was observed against CK-1δ, and a co-crystal of compound 12 inside GSK-3β confirmed a covalent interaction between cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors towards GSK-3β...
December 12, 2018: ChemMedChem
Sandrine Le Houedec, Aubin Thibault de Chanvalon, Aurélia Mouret, Edouard Metzger, Patrick Launeau, Pierre Gaudin, Thierry Lebeau
Siderophores are natural metal chelating agents that strongly control the biogeochemical metal cycles such as Fe in the environment. This article describes a new methodology to detect and quantify at the micromolar concentration the spatial distribution at millimetre scale of siderophores within the root's system. The "universal" CAS assay originally designed for bacterial siderophores detection and later designed for fungus was adapted here for diffusive equilibrium in thin film gel techniques (DET)...
December 14, 2018: Analytical Chemistry
Guo Zou, Li Zhao, Longwei Zeng, Kaijun Luo, Hailiang Ni, Haifeng Wang, Quan Li, Wenhao Yu, Xuelian Li
In this paper, we have designed and synthesized a series of neutral liquid-crystalline iridium(III) complexes based on polycatenar 2,5-diphenylpyridine and pyridyltetrazolate derivatives. Iridium(III) complexes all display highly emissive behavior with photoluminescence quantum yields in the range of 0.45-0.66 and a maximum emission wavelength at ∼563 nm. Hexagonal columnar mesophases of iridium(III) complexes can be obtained by changing the number and length of peripheral alkoxyl chains attached to a 2,5-diphenylpyridine ligand (main ligand) and a pyridyltetrazolate ligand (auxiliary ligand)...
December 14, 2018: Inorganic Chemistry
Joao Marcelo Lamim Ribeiro, Sun-Ting Tsai, Debabrata Pramanik, Yihang Wang, Pratyush Tiwary
Large parallel gains in the development of both computational resources as well as sampling methods have now made it possible to simulate dissociation events in ligand-protein complexes with all--atom resolution. Such encouraging progress, together with the inherent spatiotemporal resolution associated with molecular simulations, has left their use for investigating dissociation processes brimming with potential, both in rational drug design, where it can be an invaluable tool for determining the mechanistic driving forces behind dissociation rate constants, as well as in force-field development, where it can provide a catalog of transient molecular structures on which to refine force-fields...
December 14, 2018: Biochemistry
Farzin Sohraby, Milad Bagheri, Hassan Aryapour
Drug repurposing has become one of the most widely used methods that can make drug discovery more efficient and less expensive. Additionally, computational methods such as structure-based drug designing can be utilized to make drug discovery more efficient and more accurate. Now imagine what can be achieved by combining drug repurposing and computational methods together in drug discovery, "in silico repurposing." In this chapter, we tried to describe a method that combines structure-based virtual screening and molecular dynamics simulation which can find effective compounds among existing drugs that may affect on a specific molecular target...
2019: Methods in Molecular Biology
Zoe V Schofield, Daniel Croker, Avril A B Robertson, Nicholas L Massey, Chantal Donovan, Ernest Tee, David Edwards, Trent M Woodruff, Reena Halai, Philip M Hansbro, Matthew A Cooper
Short chain fatty acids (SCFAs) are protective against inflammatory diseases. Free fatty acid receptor 2 (FFA2), is a target of SCFAs however, their selectivity for FFA2 over other FFA receptors is limited. This study aimed to functionally characterise 2-(4-chlorophenyl)-3-methyl-N-(thiazole-2-yl)butanamide (4CMTB) and 4-((4-(2-chlorophenyl)thiazole-2-yl)amino)-4oxo-3-phenylbutanoic acid (2CTAP), and their enantiomers, in modulating FFA2 activity. The racemic mixture (R/S) and its constituents (R-) and (S-) 4CMTB or 2CTAP were used to stimulate human (h)FFA2 in the absence or presence of acetate...
December 13, 2018: Scientific Reports
Lucas A Defelipe, Juan Pablo Arcon, Carlos P Modenutti, Marcelo A Marti, Adrián G Turjanski, Xavier Barril
Simulations of molecular dynamics (MD) are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: Binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals solvent structures and preferential interaction sites (hot spots) on the protein surface. The information provided by water and its cosolvents can be used very effectively to understand protein ligand recognition and to improve the predictive capability of well-established methods such as molecular docking...
December 11, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Michael Oluwatoyin Daniyan, Oluwatoyin Tolulope Ojo
Plasmodium falciparum heat shock protein 90 (PfHsp90) has been investigated as a potential target of antimalarial drug action using naturally occurring compounds. In this study, we performed in silico screening of 236 phytochemicals of Azadirachta indica, a plant known to possess antimalarial activity, and identified fourteen (14) potential non-carcinogenic, non-mutagenic, non-teratogenic and non-genotoxic phytochemicals. These phytochemicals were docked into the ATP-binding site of PfHsp90 using Autodock vina, and docked poses were rescored using PLANTS ChemPlp, X-Score version 1...
December 4, 2018: Journal of Molecular Graphics & Modelling
Yang Xiong, Zhuanzhuan Du, Haohua Chen, Zhao Yang, Qiuyuan Tan, Changhui Zhang, Lei Zhu, Yu Lan, Min Zhang
A novel chiral phosphine-urea bifunctional ligand has been developed for Cu-catalyzed asymmetric 1,3-dipolar cycloaddition of iminoesters with methacrylonitrile, a long-standing challenging substrate in asymmetric catalysis. Distortion-interaction energy analysis based on density functional theory (DFT) calculations reveals that the distortion energy plays an important role in the observed enantioselectivity, which can be attributed to the steric effect between the phosphine ligand and the dipole reactant. DFT calculations also indicate that nucleophilic addition is the enantioselectivity-determining step and hydrogen bonding between the urea moiety and methacrylonitrile assists in control of the diastereo- and enantioselectivity...
December 13, 2018: Journal of the American Chemical Society
Yannan Li, Li Yang, Mengqi Du, Guanjun Chang
A novel fluorescent probe for Pd2+ based on the BODIPY fluorophore exploiting the PET (Photoinduced Electron Transfer) mechanism was designed and successfully synthesized. The fluorescent probe 1 was prepared by introducing m-bisimidazolylbenzene which was connected by phenyl acetylene to the BODIPY dye at the meso position. It exhibited a rapid response and high sensitivity and selectivity toward Pd2+. Probe 1 presented a rapid quenched fluorescence response in aqueous buffer media (pH 5.5) and the detection limit estimated from the titration results was 2...
December 13, 2018: Analyst
Petko St Petkov, Volodymyr Bon, Claire L Hobday, Agnieszka B Kuc, Patrick Melix, Stefan Kaskel, Tina Düren, Thomas Heine
Metal-organic frameworks (MOFs) are coordination networks with organic ligands containing potential voids. Some MOFs show pronounced structural flexibility that may result in closing and re-opening these pores. Here, we show that collective flexibility in a MOF-DUT-8(Ni) - is controlled by conformational isomerism. DUT-8(Ni), a pillared-layer MOF with Ni2 paddle-wheels, dabco pillars and naphthalene dicarboxylate (ndc) linkers, can crystallize in many conformational isomers that depend on the orientation of the non-linear ndc linkers with respect to each other...
December 13, 2018: Physical Chemistry Chemical Physics: PCCP
Euihyun Lee, Sang-Hee Shim, Minhaeng Cho
Fluorescent proteins contain an internal chromophore constituted of amino acids or an external chromophore covalently bonded to the protein. To increase their fluorescence intensities, many research groups have attempted to mutate amino acids within or near the chromophore. Recently, a new type of fluorescent protein, called UnaG, in which the ligand binds to the protein through many noncovalent interactions was discovered. Later, a series of mutants of the UnaG protein were introduced, which include eUnaG with valine 2 mutated to leucine emitting significantly stronger fluorescence than the wild type and V2T mutant, in which valine 2 is mutated to threonine, emitting weaker fluorescence than the wild type...
November 28, 2018: Chemical Science
Chong Liu, Svetlana V Eliseeva, Tian-Yi Luo, Patrick F Muldoon, Stéphane Petoud, Nathaniel L Rosi
We successfully demonstrate that metal-organic frameworks (MOFs) can be designed to be excited and emit within the biological diagnostic window (650-1450 nm). An isoreticular series of anionic rare earth MOFs with fcu topology was synthesized using 10 different rare earth elements (Y3+ , Eu3+ , Gd3+ , Tb3+ , Dy3+ , Ho3+ , Er3+ , Tm3+ , Yb3+ , Lu3+ ) and common linear ditopic ligands. Five different cationic dye molecules were incorporated into the MOFs via ion exchange. When LDS 750, which exhibits low-energy absorption in the range 450-770 nm, is loaded into an Yb3+ -MOF, it can be used as an antenna to sensitize the near-infrared (NIR) emission of Yb3+ centred at 980 nm...
November 14, 2018: Chemical Science
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