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https://www.readbyqxmd.com/read/29691292/phenformin-induced-mitochondrial-dysfunction-sensitizes-hepatocellular-carcinoma-for-dual-inhibition-of-mtor
#1
Sonia Rosa Veiga, Xuemei Ge, Carol A Mercer, María Isabel Hernández-Alvarez, Hala Elnakat Thomas, Javier Hernández-Losa, Santiago Ramón Y Cajal, Antonio Zorzano, George Thomas, Sara C Kozma
PURPOSE: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mammalian target of rapamycin (mTOR) for the treatment of HCC. However, such inhibitors induce glycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor Phenformin could reverse both side effects, impose an energetic-stress on cancer cells and suppress the growth of HCC...
April 24, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29691279/assessment-of-the-molecular-mechanisms-of-action-of-novel-4-phenylpyridine-2-one-and-6-phenylpyrimidin-4-one-allosteric-modulators-at-the-m1-muscarinic-acetylcholine-receptors
#2
Emma T van der Westhuizen, Arthur Spathis, Elham Khajehali, Maneula Jorg, Shailesh N Mistry, Ben Capuano, Andrew B Tobin, Patrick M Sexton, Peter J Scammells, Celine Valant, Arthur Christopoulos
Positive allosteric modulators (PAMs) that target the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) are potential treatments for cognitive deficits in conditions such as Alzheimer's disease and schizophrenia. We recently reported novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one M1 mAChR PAMs with the potential to display different modes of positive allosteric modulation and/or agonism (Mistry et al., 2016), but their molecular mechanisms of action remain undetermined. The current study compared the pharmacology of three such novel PAMs with the prototypical first-generation PAM, BQCA, in a recombinant Chinese hamster ovary (CHO) cell line stably expressing the human M1 mAChR...
April 24, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29691138/targeting-lysine-specific-demethylase-4a-kdm4a-tandem-tudor-domain-a-fragment-based-approach
#3
Anup K Upadhyay, Russell A Judge, Leiming Li, Ron Pithawalla, Justin Simanis, Pierre M Bodelle, Violeta L Marin, Rodger F Henry, Andrew M Petros, Chaohong Sun
The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays...
April 19, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29690896/marine-derived-protein-kinase-inhibitors-for-neuroinflammatory-diseases
#4
REVIEW
Chong Ning, Hui-Min David Wang, Rong Gao, Yu-Chia Chang, Fengqing Hu, Xianjun Meng, Shi-Ying Huang
Neuroinflammation is primarily characterized by overexpression of proinflammatory mediators produced by glial activation or immune cell infiltration. Several kinases have been shown to be critical mediators in neuroinflammation. One of the largest groups of kinases is protein kinases, which have been the second most studied group of drug targets after G-protein-coupled receptors. Thus far, most of the approved kinase inhibitor drugs are adenosine triphosphate-competitive inhibitors with various off-target liabilities because of cross-reactivities; however, marine-derived compounds provide opportunities for discovering allosteric kinase inhibitors...
April 24, 2018: Biomedical Engineering Online
https://www.readbyqxmd.com/read/29688874/a-putative-electrophysiological-biomarker-of-auditory-sensory-memory-encoding-is-sensitive-to-pharmacological-alterations-of-excitatory-inhibitory-balance-in-male-macaque-monkeys
#5
William B Holliday, Kate Gurnsey, Robert A Sweet, Tobias Teichert
BACKGROUND: The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia...
May 2018: Journal of Psychiatry & Neuroscience: JPN
https://www.readbyqxmd.com/read/29688708/novel-allosteric-activators-for-ferroptosis-regulator-glutathione-peroxidase-4
#6
Cong Li, Xiaobing Deng, Weilin Zhang, Xiaowen Xie, Marcus Conrad, Ying Liu, José Pedro Friedmann Angeli, Luhua Lai
Glutathione peroxidase 4 (GPX4) is essential for cell membrane repair, inflammation suppression, and ferroptosis inhibition. GPX4 upregulation provides unique drug discovery opportunities for inflammation and ferroptosis-related diseases. However, rational design of protein activators is challenging. Until now, no compound has been reported to activate the enzyme activity of GPX4. Here, we identified a potential allosteric site in GPX4, and successfully found eight GPX4 activators using a novel computational strategy and experimental studies...
April 24, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29688630/the-complex-allosteric-and-redox-regulation-of-the-fumarate-hydratase-and-malate-dehydratase-reactions-of-arabidopsis-thaliana-fumarase-1-and-2-gives-clues-for-understanding-the-massive-accumulation-of-fumarate
#7
Juan Pablo Zubimendi, Andrea Martinatto, Maria Pía Valacco, Silvia Moreno, Carlos Santiago Andreo, María Fabiana Drincovich, Marcos Ariel Tronconi
Arabidopsis thaliana possesses two fumarase genes (FUM), AtFUM1 (At2g47510) encoding for the mitochondrial Krebs cycle-associated enzyme and AtFUM2 (At5g50950) for the cytosolic isoform required for fumarate massive accumulation. Here, the comprehensive biochemical studies of AtFUM1 and AtFUM2 shows that they are active enzymes with similar kinetic parameters but differential regulation. For both enzymes, fumarate hydratase (FH) activity is favored over the malate dehydratase (MD) activity; however, MD is the most regulated activity with several allosteric activators...
April 24, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29688000/correction-to-rational-design-of-novel-allosteric-dihydrofolate-reductase-inhibitors-showing-antibacterial-effects-on-drug-resistant-escherichia-coli-escape-variants
#8
Bharath Srinivasan, João V Rodrigues, Sam Tonddast-Navaei, Eugene Shakhnovich, Jeffrey Skolnick
No abstract text is available yet for this article.
April 24, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29686643/inhibition-of-mtorc1-signaling-reverts-cognitive-and-affective-deficits-in-a-mouse-model-of-parkinson-s-disease
#9
Débora Masini, Alessandra Bonito-Oliva, Maëlle Bertho, Gilberto Fisone
Non-motor symptoms, including cognitive deficits and affective disorders, are frequently diagnosed in Parkinson's disease (PD) patients and are only partially alleviated by dopamine replacement therapy. Here, we used a 6-hydroxydopamine (6-OHDA) mouse model of PD to examine the effects exerted on non-motor symptoms by inhibition of the mammalian target of rapamycin complex 1 (mTORC1), which is involved in the control of protein synthesis, cell growth, and metabolism. We show that rapamycin, which acts as an allosteric inhibitor of mTORC1, counteracts the impairment of novel object recognition...
2018: Frontiers in Neurology
https://www.readbyqxmd.com/read/29686613/essential-control-of-the-function-of-the-striatopallidal-neuron-by-pre-coupled-complexes-of-adenosine-a-2a-dopamine-d-2-receptor-heterotetramers-and-adenylyl-cyclase
#10
Sergi Ferré, Jordi Bonaventura, Wendy Zhu, Candice Hatcher-Solis, Jaume Taura, César Quiroz, Ning-Sheng Cai, Estefanía Moreno, Verónica Casadó-Anguera, Alexxai V Kravitz, Kimberly R Thompson, Dardo G Tomasi, Gemma Navarro, Arnau Cordomí, Leonardo Pardo, Carme Lluís, Carmen W Dessauer, Nora D Volkow, Vicent Casadó, Francisco Ciruela, Diomedes E Logothetis, Daniel Zwilling
The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating "Go" responses upon exposure to reward-related stimuli and "NoGo" responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29686062/synaptic-adhesion-protein-elfn1-is-a-selective-allosteric-modulator-of-group-iii-metabotropic-glutamate-receptors-in-trans
#11
Henry A Dunn, Dipak N Patil, Yan Cao, Cesare Orlandi, Kirill A Martemyanov
Functional characterization of the GPCR interactome has been focused predominantly on intracellular interactions, yet GPCRs are increasingly found in complex with extracellular proteins. Extracellular leucine-rich repeat fibronectin type III domain containing 1 (ELFN1) was recently reported to physically anchor mGluR6 and mGluR7 across retinal and hippocampal synapses, respectively; however, the consequence of transsynaptic interactions on properties and pharmacology of these receptors are unknown. In the current study, we explore the effects of ELFN1 on mGluR signaling and pharmacology...
April 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29685684/characterization-of-protease-activated-receptor-par-ligands-parmodulins-are-reversible-allosteric-inhibitors-of-par1-driven-calcium-mobilization-in-endothelial-cells
#12
Disha M Gandhi, Mark W Majewski, Ricardo Rosas, Kaitlin Kentala, Trevor J Foster, Eric Greve, Chris Dockendorff
Several classes of ligands for Protease-Activated Receptors (PARs) have shown impressive anti-inflammatory and cytoprotective activities, including PAR2 antagonists and the PAR1-targeting parmodulins. In order to support medicinal chemistry studies with hundreds of compounds and to perform detailed mode-of-action studies, it became important to develop a reliable PAR assay that is operational with endothelial cells, which mediate the cytoprotective effects of interest. We report a detailed protocol for an intracellular calcium mobilization assay with adherent endothelial cells in multiwell plates that was used to study a number of known and new PAR1 and PAR2 ligands, including an alkynylated version of the PAR1 antagonist RWJ-58259 that is suitable for the preparation of tagged or conjugate compounds...
April 6, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29684708/structural-based-design-synthesis-and-antitumor-activity-of-novel-alloxazine-analogues-with-potential-selective-kinase-inhibition
#13
Waleed H Malki, Ahmed M Gouda, Hamdy E A Ali, Rabaa Al-Rousan, Doaa Samaha, Ashraf N Abdalla, Juan Bustamante, Zakaria Y Abd Elmageed, Hamed I Ali
Protein kinases are promising therapeutic targets for cancer therapy. Here, we applied multiple approaches to optimize the potency and selectivity of our reported alloxazine scaffold. Flexible moieties at position 2 of the hetero-tricyclic system were incorporated to fit into the ATP binding site and extend to the adjacent allosteric site and selectively inhibit protein kinases. This design led to potential selective inhibition of ABL1, CDK1/Cyclin A1, FAK, and SRC kinase by 30-59%. Cytotoxicity was improved by ∼50 times for the optimized lead (10b; IC50  = 40 nM) against breast cancer (MCF-7) cells...
April 17, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29684528/oligomerization-and-cooperativity-in-gpcrs-from-the-perspective-of-the-angiotensin-at1-and-dopamine-d2-receptors
#14
REVIEW
Serdar Durdagi, Ismail Erol, Ramin Ekhteiari Salmas, Busecan Aksoydan, Isik Kantarcioglu
G Protein-Coupled Receptors (GPCRs) can form homodimer or constitute heterodimer/higher oligomeric clusters with other heptahelical GPCRs. In this article, multiscale molecular modeling approaches as well as experimental techniques which are used to study oligomerization of GPCRs are reviewed. In particular, the effect of dimerization/oligomerization to the ligand binding affinity of individual protomers and also on the efficacy of the oligomer are discussed by including diverse examples from the literature...
April 20, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29684503/dynamics-based-community-analysis-and-perturbation-response-scanning-of-allosteric-interaction-networks-in-the-trap1-chaperone-structures-dissect-molecular-linkage-between-conformational-asymmetry-and-sequential-atp-hydrolysis
#15
Gennady M Verkhivker
Allosteric interactions of the Hsp90 chaperones with cochaperones and diverse protein clients can often exhibit distinct asymmetric features that determine regulatory mechanisms and cellular functions in many signaling networks. The recent crystal structures of the mitochondrial Hsp90 isoform TRAP1 in complexes with ATP analogs have provided first evidence of significant asymmetry in the closed dimerized state that triggers independent activity of the chaperone protomers, whereby preferential hydrolysis of the buckled protomer is followed by conformational flipping between protomers and hydrolysis of the second protomer...
April 20, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29683647/structure-activity-relationships-of-pan-g%C3%AE-q-11-coupled-muscarinic-acetylcholine-receptor-positive-allosteric-modulators
#16
Alice Berizzi, Aaron M Bender, Craig W Lindsley, P Jeffrey Conn, Patrick M Sexton, Christopher Langmead, Arthur Christopoulos
Recent years have seen a large increase in the discovery of allosteric ligands targeting muscarinic acetylcholine receptors (mAChRs). One of the challenges in screening such compounds is to understand their mechanisms of action and define appropriate parameter estimates for affinity, cooperativity and efficacy. Herein we describe the mechanisms of action and structure-activity relationships for a series of "pan-Gq-coupled" muscarinic acetylcholine (ACh) receptor (mAChR) positive allosteric modulators (PAMs)...
April 23, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29683646/pf-06827443-displays-robust-allosteric-agonist-and-positive-allosteric-modulator-activity-in-high-receptor-reserve-and-native-systems
#17
Sean P Moran, Hyekyung P Cho, James Maksymetz, Daniel H Remke, Ryan M Hanson, Colleen M Niswender, Craig W Lindsley, Jerri M Rook, P Jeffrey Conn
Positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M1 PAMs may reduce efficacy and contribute to adverse effect liability. However, the M1 PAM PF-06827443 was reported to have only weak agonist activity at human M1 receptors but produced M1-dependent adverse effects...
April 23, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29683325/a-thieno-2-3-d-pyrimidine-scaffold-is-a-novel-negative-allosteric-modulator-of-the-dopamine-d2-receptor
#18
Tim John Fyfe, Barbara Zarzycka, Herman D Lim, Barrie Kellam, Shailesh N Mistry, Vsevolod Katritch, Peter J Scammells, J Robert Lane, Ben Capuano
Recently, a novel negative allosteric modulator (NAM) of the D2 -like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3- d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, whilst functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles...
April 23, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29681796/surface-expression-function-and-pharmacology-of-disease-associated-mutations-in-the-membrane-domain-of-the-human-glun2b-subunit
#19
Vojtech Vyklicky, Barbora Krausova, Jiri Cerny, Marek Ladislav, Tereza Smejkalova, Bohdan Kysilov, Miloslav Korinek, Sarka Danacikova, Martin Horak, Hana Chodounska, Eva Kudova, Ladislav Vyklicky
N-methyl-D-aspartate receptors (NMDARs), glutamate-gated ion channels, mediate signaling at the majority of excitatory synapses in the nervous system. Recent sequencing data for neurological and psychiatric patients have indicated numerous mutations in genes encoding for NMDAR subunits. Here, we present surface expression, functional, and pharmacological analysis of 11 de novo missense mutations of the human hGluN2B subunit (P553L; V558I; W607C; N615I; V618G; S628F; E657G; G820E; G820A; M824R; L825V) located in the pre-M1, M1, M2, M3, and M4 membrane regions...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29681499/allosteric-activation-dictates-prc2-activity-independent-of-its-recruitment-to-chromatin
#20
Chul-Hwan Lee, Jia-Ray Yu, Sunil Kumar, Ying Jin, Gary LeRoy, Natarajan Bhanu, Syuzo Kaneko, Benjamin A Garcia, Andrew D Hamilton, Danny Reinberg
PRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here we report a stepwise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found to be mutated in cancers and/or Weaver syndrome...
April 13, 2018: Molecular Cell
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