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https://www.readbyqxmd.com/read/28431342/discovery-of-tetrahydrocarbazoles-as-dual-perk-and-prb-inhibitors
#1
Mahesh R Kulkarni, Madhav S Mane, Usha Ghosh, Rajiv Sharma, Nitin P Lad, Ankita Srivastava, Asha Kulkarni-Almeida, Prashant S Kharkar, Vijay M Khedkar, Shivaji S Pandit
The extracellular signal-regulated kinase (ERK) is one of the most important molecular targets for cancer that controls diverse cellular processes such as proliferation, survival, differentiation and motility. Similarly, the Rb (retinoblastoma protein) is a tumor suppressor protein and its function is to prevent excessive cell growth by inhibiting cell cycle progression. When the cell is ready to divide, pRb is phosphorylated, becomes inactive and allows cell cycle progression. Herein, we discovered a new series of tetrahydrocarbazoles as dual inhibitors of pERK and pRb phosphorylation...
March 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28431259/allosteric-regulation-of-metabolism-in-cancer-endogenous-mechanisms-and-considerations-for-drug-design
#2
REVIEW
Jamie A Macpherson, Dimitrios Anastasiou
Alterations in metabolic processes have been linked to various diseases, including cancer. Although gene expression can dictate long-term metabolic adaptation, many metabolic changes found in cancer are associated with altered allosteric properties of the underlying enzymes. Small molecule-protein interactions and intracellular signalling converge to orchestrate these allosteric mechanisms, which, emerging evidence suggests, constitute a promising therapeutic avenue. In this review we focus on glucose and energy metabolism to illustrate the role of allostery in cancer physiology and we discuss approaches to streamline the process of targeting aberrant allosteric pathways with small molecules...
April 18, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28431241/akt-pkb-signaling-navigating-the-network
#3
REVIEW
Brendan D Manning, Alex Toker
The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431213/genome-mining-unearths-a-hybrid-nonribosomal-peptide-synthetase-like-pteridine-synthase-biosynthetic-gene-cluster
#4
Hyun Bong Park, Corey E Perez, Karl W Barber, Jesse Rinehart, Jason M Crawford
Nonribosomal peptides represent a large class of metabolites with pharmaceutical relevance. Pteridines, such as pterins, folates, and flavins, are heterocyclic metabolites that often serve as redox-active cofactors. The biosynthetic machineries for construction of these distinct classes of small molecules operate independently in the cell. Here, we discovered an unprecedented nonribosomal peptide synthetase-like-pteridine synthase hybrid biosynthetic gene cluster in Photorhabdus luminescens using genome synteny analysis...
March 15, 2017: ELife
https://www.readbyqxmd.com/read/28431169/spa-ln-a-scoring-function-of-ligand-nucleic-acid-interactions-via-optimizing-both-specificity-and-affinity
#5
Zhiqiang Yan, Jin Wang
Nucleic acids have been widely recognized as potential targets in drug discovery and aptamer selection. Quantifying the interactions between small molecules and nucleic acids is critical to discover lead compounds and design novel aptamers. Scoring function is normally employed to quantify the interactions in structure-based virtual screening. However, the predictive power of nucleic acid-ligand scoring functions is still a challenge compared to other types of biomolecular recognition. With the rapid growth of experimentally determined nucleic acid-ligand complex structures, in this work, we develop a knowledge-based scoring function of nucleic acid-ligand interactions, namely SPA-LN...
April 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28430987/rab32-subfamily-small-gtpases-pleiotropic-rabs-in-endosomal-trafficking
#6
Norihiko Ohbayashi, Mitsunori Fukuda, Yasunori Kanaho
Rab small GTPases, well-known regulators of membrane trafficking pathways in eukaryotic cells, comprise approximately 60 different members in mammals. During the past decade, our understanding of the functions of mammalian Rab32 subfamily members (Rab32 and Rab38) have deepened, especially on the biogenesis of lysosome-related organelles, such as melanosomes, and the protection mechanisms against several pathogenic microbial infections. Endosome-mediated membrane trafficking by Rab32 subfamily members plays pivotal roles in these events...
April 14, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/28430982/evidence-of-nuclei-encoded-spliceosome-mediating-splicing-of-mitochondrial-rna
#7
Roberto H Herai, Priscilla D Negraes, Alysson R Muotri
Mitochondria are thought to have originated as free-living prokaryotes. Mitochondria organelles have small circular genomes with substantial structural (absence of histones and introns) and genetic similarity to bacteria. Contrary to the prevailing concept of intronless mitochondria, here we present evidences that mitochondrial RNA transcripts (mtRNA) are not limited to policystronic molecules, but also processed as nuclei-like transcripts that are differentially spliced and expressed in a cell-type specific manner...
April 19, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28430857/repurposed-drugs-targeting-eif2%C3%AE-p-mediated-translational-repression-prevent-neurodegeneration-in-mice
#8
Mark Halliday, Helois Radford, Karlijn A M Zents, Collin Molloy, Julie A Moreno, Nicholas C Verity, Ewan Smith, Catharine A Ortori, David A Barrett, Martin Bushell, Giovanna R Mallucci
Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss...
April 19, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28430604/signal-transducing-adaptor-protein-2-promotes-generation-of-functional-long-term-memory-cd8-t-cells-by-preventing-terminal-effector-differentiation
#9
Daisuke Muraoka, Naohiro Seo, Tae Hayashi, Chisaki Hyuga-Amaike, Kana Okamori, Isao Tawara, Naozumi Harada, Hiroshi Shiku
Long-surviving memory CD8+ T cells generated by stimulation with appropriate tumor-associated antigens are the most aggressive and persistent tumoricidal effectors. In this event of memory CD8+ T cell development, the signal transducer and activator of transcription (STAT) proteins function as the crucial intracellular signaling molecules, but the regulatory mechanism of STATs in CD8+ T cells is not fully understood. In this study, we report for the first time, by using murine vaccination models, that signal-transducing adaptor protein-2 (STAP2) maintains the cytotoxicity of long-lived memory CD8+ T cells by controlling a STAT3/suppressor of cytokine signaling 3 (SOCS3) cascade...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430444/molecular-structuring-and-percolation-transition-in-hydrated-sulfonated-poly-ether-ether-ketone-membranes
#10
Madhusmita Tripathy, Sunil Kumar P B, Abhijit P Deshpande
The extent of phase separation and water percolation in sulfonated membranes are the key to their performance in fuel cells. Toward this, the effect of hydration on the morphology and transport characteristics of sulfonated poly(ether ether ketone), sPEEK, membrane is investigated using atomistic molecular dynamics simulation at various hydration levels($\lambda$: number of water molecules per sulfonate group). The evolution of local morphology is investigated using structural correlations and minimum pair distances...
April 21, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28430432/absolute-binding-free-energies-between-t4-lysozyme-and-141-small-molecules-calculations-based-on-multiple-rigid-receptor-configurations
#11
Bing Xie, Trung Hai Nguyen, David D L Minh
We demonstrate the feasibility of estimating protein-ligand binding free energies using multiple rigid receptor configurations. Based on T4 lysozyme snapshots extracted from six alchemical binding free energy calculations with a flexible receptor, binding free energies were estimated for a total of 141 ligands. For 24 ligands, the calculations reproduced flexible-receptor estimates with a correlation coefficient of 0.90 and a root mean square error of 1.59 kcal/mol. The accuracy of calculations based on Poisson-Boltzmann/Surface Area implicit solvent was comparable to previously reported free energy calculations...
April 21, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28430426/the-rosetta-all-atom-energy-function-for-macromolecular-modeling-and-design
#12
Rebecca Faye Alford, Andrew Leaver-Fay, Jeliazko R Jeliazkov, Matthew J O'Meara, Frank P DiMaio, Hahnbeom Park, Maxim V Shapovalov, P Douglas Renfrew, Vikram Khipple Mulligan, Kalli Kappel, Jason W Labonte, Michael Steven Pacella, Richard Bonneau, Philip Bradley, Roland L Dunbrack, Rhiju Das, David Baker, Brian Kuhlman, Tanja Kortemme, Jeffrey J Gray
Over the past decade, the Rosetta biomolecular modeling suite has informed diverse biological questions and engineering challenges ranging from interpretation of low-resolution structural data to design of nanomaterials, protein therapeutics, and vaccines. Central to Rosetta's success is the energy function: a model parameterized from small molecule and X-ray crystal structure data used to approximate the energy associated with each biomolecule conformation. This paper describes the mathematical models and physical concepts that underlie the latest Rosetta Energy Function, REF15...
April 21, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28430418/effects-of-small-polar-molecules-ma-and-h2o-on-degradation-processes-of-perovskite-solar-cells
#13
Chunqing Ma, Dong Shen, Jian Qing, Hrisheekesh Thachoth Chandran, Ming-Fai Lo, Chun-Sing Lee
Degradation mechanisms of methylammonium lead halide perovskite solar cells (PSCs) have drawn much attention recently. Herein, the bulk and surface degradation processes of the perovskite were differentiated for the first time by employing combinational studies using electrochemical impedance spectroscopy (EIS), capacitance frequency (CF), and X-ray diffraction (XRD) studies with particular attention on the roles of small polar molecules (MA(+) and H2O). CF study shows that short-circuit current density of the PSCs is increased by H2O at the beginning of the degradation process coupled with an increased surface capacitance...
April 21, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28430366/cyclic-rgd-penta-peptides-crgdyk-derivatized-with-cyclopentadienyl-complexes-of-technetium-and-rhenium-as-radiopharmaceutical-probes
#14
Qaisar Nadeem, Yunjun Shen, Muhammad Farooq Warsi, Gulfam Nasar, Muhammad Abdul Qadir, Roger Alberto
The present study reports the syntheses of half-sandwich complexes of the type [M(η(5) -C5 H4 CONH-R)(CO)3 ] (M = Re,(99m) Tc;R = cyclic RGD peptide (cRGDyK) for potential imaging of αv β3 integrin expression. The (99m) Tc complex was prepared directly from the reaction of [(99m) Tc(OH2 )3 (CO)3 ](+) with cRGDyK, doubly conjugated to Thiele's acid [(C5 H5 COOH)2 ] in water. This approach extends the viability of metal-mediated retro Diels-Alder reactions for the preparation of small molecules such as linear tripeptides to a more complex cyclic peptide carrying a [(η(5) -C5 H4 )(99m) Tc(CO)3 ] tag...
April 21, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28430357/reactive-oxygen-species-key-regulators-in-vascular-health-and-diseases
#15
REVIEW
Qishan Chen, Qiwen Wang, Jianhua Zhu, Qingzhong Xiao, Li Zhang
Reactive oxygen species (ROS) are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. In the vascular system, physiological levels of ROS are essential for normal vascular functions including endothelial homeostasis and smooth muscle cell contraction. In contrast, uncontrolled overproduction of ROS resulted from imbalance of ROS generation and elimination, leads to the development of vascular diseases. Excessive ROS cause vascular cell damages, recruitment of inflammatory cells, lipid peroxidation, activation of metalloproteinases, and deposition of extracellular matrix, collectively leading to vascular remodeling...
April 21, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28430138/nanomaterials-as-assisted-matrix-of-laser-desorption-ionization-time-of-flight-mass-spectrometry-for-the-analysis-of-small-molecules
#16
REVIEW
Minghua Lu, Xueqing Yang, Yixin Yang, Peige Qin, Xiuru Wu, Zongwei Cai
Matrix-assisted laser desorption/ionization (MALDI), a soft ionization method, coupling with time-of-flight mass spectrometry (TOF MS) has become an indispensible tool for analyzing macromolecules, such as peptides, proteins, nucleic acids and polymers. However, the application of MALDI for the analysis of small molecules (<700 Da) has become the great challenge because of the interference from the conventional matrix in low mass region. To overcome this drawback, more attention has been paid to explore interference-free methods in the past decade...
April 21, 2017: Nanomaterials
https://www.readbyqxmd.com/read/28429943/on-the-size-and-origins-of-long-range-orientational-water-correlations-in-dilute-aqueous-salt-solutions
#17
Eva Pluharova, Damien Laage, Pavel Jungwirth
Long-range ordering of water around solutes has been invoked repeatedly in the literature as the key to understanding its biological function. Recently, it has been shown that in a dilute 8 mM aqueous NaCl solution the orientational correlation between water molecules extends beyond 8 nanometers. This was interpreted as arising from a long-range effect induced by the ions on the water collective hydrogen-bond interactions. Within this interpretation, each ion was supposed to affect tens of thousands or more water molecules in its surroundings, invoking a picture of ordered domains extending to several nanometers...
April 21, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28429938/high-resolution-accurate-mass-mass-spectrometry-enables-in-depth-characterization-of-in-vivo-biotransformations-for-intact-antibody-drug-conjugates
#18
Jintang He, Dian Su, Carl K Ng, Luna Liu, Shang-Fan Yu, Thomas H Pillow, Geoffrey Del Rosario, Martine Darwish, Byoung-Chul Lee, Rachana Ohri, Hongxiang Zhou, Xueji Wang, Jiawei Lu, Surinder Kaur, Keyang Xu
Antibody-drug conjugates (ADCs) represent a promising class of therapeutics for the targeted delivery of highly potent cytotoxic drugs to tumor cells to improve bioactivity while minimizing side effects. ADCs are composed of both small and large molecules, and therefore have complex molecular structures. In vivo biotransformations may further increase the complexity of ADCs, representing a unique challenge for bioanalytical assays. Quadrupole time-of-flight mass spectrometry (Q-TOF MS) with electrospray ionization has been widely used for characterization of intact ADCs...
April 21, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28429811/synthesis-and-structural-characterisation-of-the-aggregates-of-benzo-1-2-chalcogenazole-2-oxides
#19
Peter C Ho, Jamal Rafique, Jiwon Lee, Lucia M Lee, Hilary A Jenkins, James F Britten, Antonio L Braga, Ignacio Vargas-Baca
Iodine oxidation of bis[2-(hydroxyiminomethyl)phenyl] dichalcogenides yields benzo-1,2-chalcogenazole 2-oxides. Annulated derivatives of iso-tellurazole N-oxides spontaneously aggregate into cyclic tetra- and hexamers through TeO chalcogen bonding; the structures of the co-crystals with benzene and CH2Cl2 illustrate the ability of these macrocycles to interact with small guest molecules. The selenium congener crystallizes forming a supramolecular polymer. VT NMR indicates that both compounds aggregate in solution but only at low temperature in the selenium case...
April 21, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28429674/targeting-the-role-of-lipoprotein-a-in-stroke
#20
Mahdi Garelnabi, Zahra Mazhar, Andrew Hughes
Stroke is the third leading cause of death in the United States, behind only heart disease and cancer, with over 140,000 associated deaths per year. Considerable research is ongoing to examine the role of modifiable risk factors which may cause or contribute to a stroke occurring. Although age and family history are generally considered to be major risk factors, there are several modifiable and non-modifiable risk factors that are linked to the pathogenesis of a stroke. Lipoprotein (a), or Lp(a), is a type of low-density lipoprotein containing an integral apoB100 component with an attached ApoA1 isoform via a disulfide linkage...
April 21, 2017: Cardiovascular & Hematological Disorders Drug Targets
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