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Small molecule structure

Jingjing Wu, Paula Lorenzo, Siying Zhong, Muhammad Ali, Craig P Butts, Eddie L Myers, Varinder K Aggarwal
Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines. Sometimes we happen upon such molecules in minute quantities in unique, difficult-to-reach, and often fleeting environments, perhaps never to be discovered again. In these cases, determining the structure of a molecule-including assigning its relative and absolute configurations-is paramount, enabling one to understand its biological activity. Molecules that comprise stereochemically complex acyclic and conformationally flexible carbon chains make such a task extremely challenging...
July 26, 2017: Nature
Abid Hussain, Ana T S Semeano, Susana I C J Palma, Ana S Pina, José Almeida, Bárbara F Medrado, Ana C C S Pádua, Ana L Carvalho, Madalena Dionísio, Rosamaria W C Li, Hugo Gamboa, Rein V Ulijn, Jonas Gruber, Ana C A Roque
The cooperative assembly of biopolymers and small molecules can yield functional materials with precisely tunable properties. Here, the fabrication, characterization, and use of multicomponent hybrid gels as selective gas sensors are reported. The gels are composed of liquid crystal droplets self-assembled in the presence of ionic liquids, which further coassemble with biopolymers to form stable matrices. Each individual component can be varied and acts cooperatively to tune gels' structure and function. The unique molecular environment in hybrid gels is explored for supramolecular recognition of volatile compounds...
July 19, 2017: Advanced Functional Materials
Vilius Kurauskas, Sergei A Izmailov, Olga N Rogacheva, Audrey Hessel, Isabel Ayala, Joyce Woodhouse, Anastasya Shilova, Yi Xue, Tairan Yuwen, Nicolas Coquelle, Jacques-Philippe Colletier, Nikolai R Skrynnikov, Paul Schanda
Proteins perform their functions in solution but their structures are most frequently studied inside crystals. Here we probe how the crystal packing alters microsecond dynamics, using solid-state NMR measurements and multi-microsecond MD simulations of different crystal forms of ubiquitin. In particular, near-rotary-resonance relaxation dispersion (NERRD) experiments probe angular backbone motion, while Bloch-McConnell relaxation dispersion data report on fluctuations of the local electronic environment. These experiments and simulations reveal that the packing of the protein can significantly alter the thermodynamics and kinetics of local conformational exchange...
July 27, 2017: Nature Communications
Mohd Younus Bhat, Laishram Rajendrakumar Singh, Tanveer Ali Dar
Osmolytes (small molecules that help in circumventing stresses) are known to promote protein folding and prevent aggregation in the case of globular proteins. However, the effect of such osmolytes on the structure and function of intrinsically disordered proteins (IDPs) has not been clearly understood. Here we have investigated the effect of methylamine osmolytes on α-casein (an IDP present in mammalian milk) and discovered that TMAO (Trimethylamine-N-oxide) but not other methylamines renders α-casein functionless...
July 26, 2017: Scientific Reports
Bruce Carrington, William K Myers, Peter Horanyi, Mark Calmiano, Alastair D G Lawson
Double electron-electron resonance in conjunction with site-directed spin labeling has been used to probe natural conformational sampling of the human tumor necrosis factor α trimer. We suggest a previously unreported, predeoligomerization conformation of the trimer that has been shown to be sampled at low frequency. A model of this trimeric state has been constructed based on crystal structures using the double-electron-electron-resonance distances. The model shows one of the protomers to be rotated and tilted outward at the tip end, leading to a breaking of the trimerous symmetry and distortion at a receptor-binding interface...
July 25, 2017: Biophysical Journal
Takashi Nakamura, Yuya Kaneko, Eiji Nishibori, Tatsuya Nabeshima
Most biological and synthetic receptors for small organic molecules employ a combination of relatively weak intermolecular interactions such as hydrogen bonds. A host compound that utilizes stronger yet reversible bonding in a synergistic manner could realize precise recognition, but the regulation and spatial arrangement of such reactive interaction moieties have been a challenge. Here, we show a multinuclear zinc complex synthesized from a macrocyclic ligand hexapap, which inwardly arranges labile metal coordination sites for external molecules...
July 25, 2017: Nature Communications
Duo Wei, Mengting Han, Lei Yu
Characterization of selenium states by (77)Se NMR is quite important to provide vital information for mechanism studies in organoselenium-catalyzed reactions. With the development of heterogeneous polymer-supported organoselenium catalysts, the solid state (77)Se NMR comes to the spotlight. It is necessary to figure out an advanced protocol that provides good quality spectra within limited time because solid state (77)Se NMR measurements are always time consuming due to the long relaxation time and the relatively low sensitivity...
July 25, 2017: Scientific Reports
Yun-Rong Gao, De-Feng Li, Joy Fleming, Ya-Feng Zhou, Ying Liu, Jiao-Yu Deng, Lin Zhou, Jie Zhou, Guo-Feng Zhu, Xian-En Zhang, Da-Cheng Wang, Li-Jun Bi
MarR family proteins are transcriptional regulators that control expression of bacterial proteins involved in metabolism, virulence, stress responses and multi-drug resistance, mainly via ligand-mediated attenuation of DNA binding. Greater understanding of their underlying regulatory mechanism may open up new avenues for the effective treatment of bacterial infections. To gain molecular insight into the mechanism of Rv2887, a MarR family protein in M. tuberculosis, we first showed that it binds salicylate (SA) and para-aminosalicylic acid (PAS), its structural analogue and an antitubercular drug, in a 1:1 stoichiometry with high affinity...
July 25, 2017: Scientific Reports
Sunniya Iftikhar, Sardraz Khan, Aishah Bilal, Safia Manzoor, Muhammad Abdullah, Abdel-Hamid Emwas, Salim Sioud, Xin Gao, Ghayoor Abbas Chotana, Amir Faisal, Rahman Shah Zaib Saleem
Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation...
July 15, 2017: Bioorganic & Medicinal Chemistry Letters
Dmitrii V Kalinin, Ralph Holl
The Zn(2+)-dependent deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising target for the development of antibiotics selectively combating Gram-negative pathogens. Researchers from industry and academia have synthesized structurally diverse LpxC inhibitors, exhibiting different LpxC inhibitory and antibacterial activities. Areas covered: A brief introduction into the structure and function of LpxC, showing its suitability as antibacterial target, along with the structures of several reported LpxC inhibitors, is given...
July 25, 2017: Expert Opinion on Therapeutic Patents
Biplab K Maiti, Rui M Almeida, Luisa B Maia, Isabel Moura, José J G Moura
Orange protein (ORP) is a small bacterial protein, of unknown function, that contains a unique molybdenum/copper heterometallic cluster, [S2Mo(VI)S2Cu(I)S2Mo(VI)S2](3-) (Mo/Cu), non-covalently bound. The native cluster can be reconstituted in a protein-assisted mode by the addition of Cu(II) plus tetrathiomolybdate to apo-ORP under controlled conditions. In the work described herein, we artificially inserted the ATCUN ("amino terminus Cu and Ni") motif in the Desulfovibrio gigas ORP (Ala1Ser2His3 followed by the native amino acid residues; modified protein abbreviated as ORP*) to increase our understanding of the Mo/Cu cluster assembly in ORP...
July 25, 2017: Inorganic Chemistry
Yan Xu, Vivian Li, Jinjiang Li, Duohai Pan, Gerd Langenbucher, Neil Mathias
Liquid crystal lipid-based formulations are an effective approach to prolong pharmacokinetics and reduce burst release of a drug on subcutaneous delivery. The objective of this paper was to investigate the influence of phase structures of a lipid-based liquid crystal delivery system and its associated mechanical properties on the release profile of a peptide. It was hypothesized that release of drug molecules are closely related to the mechanical properties that are controlled by phase structures. Experimentally, the relationship between phase structures of lipid liquid crystal system-soy phosphatidyl choline (SPC) and glycerol dioleate (GDO) in water were characterized by polarized light microscopy and small angle X-ray diffraction...
July 24, 2017: AAPS PharmSciTech
J Li, Y Wu, Y Ma, N Lu, J M Regenstein, P Zhou
High-protein intermediate moisture food (HPIMF) containing sodium caseinate (NaCN) often gave a harder texture compared with that made from whey proteins or soy proteins, due to the aggregation of protein particles. The objectives of this study were to explore whether the addition of hydrocolloids could soften the texture and illustrate the possible mechanism. Three kinds of hydrocolloids, xanthan gum, κ-carrageenan, and gum arabic were chosen, and samples including of these three kinds of hydrocolloids were studied through texture analysis using a TPA test and microstructure observation by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM)...
July 25, 2017: Food & Function
Bernhard C Lechtenberg, Peter D Mace, E Hampton Sessions, Robert Williamson, Romain Stalder, Yann Wallez, Gregory P Roth, Stefan J Riedl, Elena B Pasquale
ERK is the effector kinase of the RAS-RAF-MEK-ERK signaling cascade, which promotes cell transformation and malignancy in many cancers and is thus a major drug target in oncology. Kinase inhibitors targeting RAF or MEK are already used for the treatment of certain cancers, such as melanoma. Although the initial response to these drugs can be dramatic, development of drug resistance is a major challenge, even with combination therapies targeting both RAF and MEK. Importantly, most resistance mechanisms still rely on activation of the downstream effector kinase ERK, making it a promising target for drug development efforts...
July 13, 2017: ACS Medicinal Chemistry Letters
Nadav Amdursky, M Harunur Rashid, Molly M Stevens, Irene Yarovsky
The diffusion of protons along biological surfaces and the interaction of biological structures with water are fundamental areas of interest in biology and chemistry. Here, we examine the surface of insulin amyloid fibrils and follow the binding of small molecules (photoacids) that differ according to the number and location of their sulfonic groups. We use transient fluorescence combined with a spherically-symmetric diffusion theory to show that the binding mode of different photoacids determines the efficiency of proton dissociation from the photoacid and the dimensionality of the proton's diffusion...
July 24, 2017: Scientific Reports
Yuichi Sawaguchi, Ryuta Yamazaki, Yukiko Nishiyama, Toshio Sasai, Masayuki Mae, Atsuhiro Abe, Takashi Yaegashi, Hiroyuki Nishiyama, Takeshi Matsuzaki
BACKGROUND/AIM: The serine/threonine Pim kinases are overexpressed in various types of solid carcinomas and hematological malignancies, and contribute to regulating cell-cycle progression and cell survival. The aim of this study was to discover a novel pan-Pim kinases inhibitor with potent anti-proliferative activities against cancer cell lines. MATERIALS AND METHODS: We screened a panel of small molecule compounds for their ability to inhibit Pim-1 kinase activity, and the hit compound was optimized using the docking analysis to Pim-1...
August 2017: Anticancer Research
Bharath Srinivasan, Sam Tonddast-Navaei, Jeffrey Skolnick
Traditional structure and ligand based virtual screening approaches rely on the availability of structural and ligand binding information. To overcome this limitation, hybrid approaches were developed that relied on extraction of ligand binding information from proteins sharing similar folds and hence, evolutionarily relationship. However, they cannot target a chosen pocket in a protein. To address this, a pocket centric virtual ligand screening approach is required. Here, we employ a new, iterative implementation of a pocket and ligand-similarity based approach to virtual ligand screening to predict small molecule binders for the olfactomedin domain of human myocilin implicated in glaucoma...
July 12, 2017: Bioorganic & Medicinal Chemistry Letters
J Ye, Y Y He, Y Yan, J H Zhao, T Y Lian, X J Wang, Y Yan, S J Zhang, S H Yang, Z C Jing
Objective: To establish a hydrogen peroxide (H(2)O(2)) induced injury model of pulmonary artery endothelial cells (PAECs) and explore the molecular mechanisms of oxidative stress on the structure and function of PAECs in this model. Methods: Human PAECs were treated with H(2)O(2) at different concentrations (25, 50, 100, 200, 400, 800, 1 600, 3 200, 6 400 μmol/L) for 4 and 24 h, respectively. The PAECs survival curve was obtained according to the cell viability measured by CCK-8 assay. The cell apoptosis of PAECs was detected by flow cytometry...
July 24, 2017: Zhonghua Xin Xue Guan Bing za Zhi
K Nilavarasi, Thejus R Kartha, V Madhurima
At low concentrations of methanol in a binary system of ethanol and methanol, uniquely complex molecular interactions are reported here. Previous studies indicate that ethanol molecules form aggregates held together by hydrogen bonding (O-H-O) and also dispersive forces. Addition of small amount of methanol tends to break the hydrogen bond network of ethanol due to the larger polarity of methanol. This leads to the ethanol molecules becoming somewhat isolated from each other within a scaffolding network of methanol molecules, as seen from the present molecular dynamics simulations...
July 15, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
Alberto Ramos, Antonio Antiñolo, Fernando Carrillo-Hermosilla, Rafael Fernández-Galán, María Del Pilar Montero-Rama, Elena Villaseñor, Antonio Rodríguez-Diéguez, Daniel García-Vivó
We report here 1,1- and 1,2-insertion reactions of small unsaturated molecules in the N-B bonds of two boron guanidinates, (Me2N)C(N(i)Pr)2BCy2 (1) and {(i)Pr(H)N}C(N(i)Pr){N(p-(t)Bu-C6H4)}BCy2 (2), and two bisboron guanidinates(2-), {(i)Pr(BCy2)N}C(N(i)Pr){N(p-(t)Bu-C6H4)}BCy2 (3) and {(i)Pr(C8H14B)N}C(N(i)Pr){N(p-Me-C6H4)}BC8H14 (4), the latter being prepared for the first time by double deprotonation of the corresponding guanidine with the 9-borabicyclo[3.3.1]nonane dimer, (H-BC8H14)2. Compounds 1-4 easily insert aromatic isonitriles, XylNC (Xyl = 2,6-Me2-C6H3) and (p-MeO-C6H4)NC, to give the expected diazaboroles 5-12, some of them being structurally characterised by X-ray diffraction...
July 24, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
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