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Bounded rationality

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https://www.readbyqxmd.com/read/29153590/heterocyclic-periphery-in-the-design-of-carbonic-anhydrase-inhibitors-1-2-4-oxadiazol-5-yl-benzenesulfonamides-as-potent-and-selective-inhibitors-of-cytosolic-hca-ii-and-membrane-bound-hca-ix-isoforms
#1
Mikhail Krasavin, Anton Shetnev, Tatyana Sharonova, Sergey Baykov, Tiziano Tuccinardi, Stanislav Kalinin, Andrea Angeli, Claudiu T Supuran
A series of novel aromatic primary sulfonamides decorated with diversely substituted 1,2,4-oxadiazole periphery groups has been prepared using a parallel chemistry approach. The compounds displayed a potent inhibition of cytosolic hCA II and membrane-bound hCA IX isoforms. Due to a different cellular localization of the two target enzymes, the compounds can be viewed as selective inhibition tools for either isoform, depending on the cellular permeability profile. The SAR findings revealed in this study has been well rationalized by docking simulation of the key compounds against the crystal structures of the relevant hCA isoforms...
October 16, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29152633/conformational-collapse-of-spherical-poly-n-isopropylacrylamide-brushes-under-the-constraint-of-bound-micelles
#2
Peng-Wei Zhu, Luguang Chen
In this paper, we investigate the micelle (charge)-constrained collapse of a spherical poly(N-isopropylacrylamide) (PNIPAM) brush. The system is an example of the transition of a short-length neutral polymer from a stretched state to a folded state under the constraint of long-range electrostatic repulsion. The collapsed state is described as an anisotropic globule comprising a cascade of rod-like or hairpin bundles. A critical aggregation number of bound micelles is obtained to distinguish the charge-induced deformation of the globule, which provides a guideline to characterize globule dimensions under different strengths of electrostatic interaction...
November 20, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29148771/an-qm-mm-study-of-the-reaction-catalyzed-by-alkyladenine-dna-glycosylase-examination-of-the-substrate-specificity-of-a-dna-repair-enzyme
#3
Stefan A P Lenz, Stacey D Wetmore
Human alkyladenine DNA glycosylase (AAG) functions as part of the base excision repair pathway to excise structurally diverse oxidized and alkylated DNA purines. Specifically, AAG uses a water molecule activated by a general base and a non-specific active site lined with aromatic residues to cleave the N-glycosidic bond. Despite broad substrate specificity, AAG does not target the natural purines (adenine (A) and guanine (G)). Using the ONIOM(QM:MM) methodology, we provide fundamental atomic level details of AAG bound to DNA-containing a neutral substrate (hypoxanthine (Hx)), a non-substrate (G), or a cationic substrate (7-methylguanine (7MeG)), and probe changes in the reaction pathway that occur when AAG targets different nucleotides...
November 17, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29148316/recognition-dynamics-of-trinuclear-copper-cluster-and-associated-histidine-residues-through-conserved-or-semi-conserved-water-molecules-in-human-ceruloplasmin-the-involvement-of-aspartic-and-glutamic-acid-gates
#4
Bishnu Prasad Mukhopadhyay
Human Ceruloplasmin belongs to the family of multi-copper oxidases and it is involved in different physiological processes, copper ion transport, iron metabolism, iron homeostasis, and biogenic amine metabolism. MD-simulation studies have indicated the higher hydrophilic susceptibility of the trinuclear copper cluster in native CP compared to its oxygen bound form. The copper (T2/T3) atom Cu3047 of the cluster, which is close to T1 copper center Cu3052 (~13 Å) has a higher affinity for water molecules compared to other copper centers...
November 17, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29145791/impact-of-novel-n-aryl-piperamide-no-donors-on-nf-%C3%AE%C2%BAb-translocation-in-neuroinflammation-rational-drug-designing-synthesis-and-biological-evaluation
#5
Sajad Shahbazi, Jagdeep Kaur, Shikha Singh, K Gopinath Achary, Sameena Wani, Sobhagyalaxmi Jema, Jabed Akhtar, Ranbir Chander Sobti
NO donor drugs showed a significant therapeutic effect in the treatment of many diseases, such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. NO-releasing anti-inflammatory drugs are the prototypes of a novel class of compounds, combining the pharmacological activities of anti-inflammatory and anti-nociceptive of drugs with those of NO, thus possessing potential therapeutic applications in a great variety of diseases. In this study, we designed and predicted biological activity by targeting cyclooxygenase type 2 (COX-2) and NF-κB subunits and pharmacological profiling along with toxicity predictions of various N-aryl piperamides linked via an ester bond to a spacer that is bound to a NO-releasing moiety (-ONO2)...
January 1, 2017: Innate Immunity
https://www.readbyqxmd.com/read/29142290/characterizing-the-conformational-landscape-of-mdm2-binding-p53-peptides-using-molecular-dynamics-simulations
#6
Shilpa Yadahalli, Jianguo Li, David P Lane, Shachi Gosavi, Chandra S Verma
The conformational landscapes of p53 peptide variants and phage derived peptide (12/1) variants, all known to bind to MDM2, are studied using hamiltonian replica exchange molecular dynamics simulations. Complementing earlier observations, the current study suggests that the p53 peptides largely follow the 'conformational selection' paradigm in their recognition of and complexation by MDM2 while the 12/1 peptides likely undergo some element of conformational selection but are mostly driven by 'binding induced folding'...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29140786/selection-of-an-anticalin%C3%A2-against-the-membrane-form-of-hsp70-via-bacterial-surface-display-and-its-theranostic-application-in-tumour-models
#7
Lars Friedrich, Petra Kornberger, Claudia T Mendler, Gabriele Multhoff, Markus Schwaiger, Arne Skerra
We describe the selection of Anticalins against a common tumour surface antigen, human Hsp70, using functional display on live E. coli cells as fusion with a truncated EspP autotransporter. While found intracellularly in normal cells, Hsp70 is frequently exposed in a membrane-bound state on the surface of tumour cells and, even more pronounced, in metastases or after radiochemotherapy. Employing a recombinant Hsp70 fragment comprising residues 383-548 as target, Anticalins were selected from a naive bacterial library...
November 27, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/29136893/study-on-molecularly-imprinted-nanoparticle-modified-microplates-for-pseudo-elisa-assays
#8
Lucia Cenci, Chiara Piotto, Paolo Bettotti, Alessandra Maria Bossi
Nanosized Molecularly Imprinted Polymers (nanoMIPs) are designed artificial nanoreceptors with a predetermined selectivity and specificity for a given analyte, lately proposed as a replacement to antibodies in immunoassays. The nanoMIP-plate preparation based on nanoparticle adsorption was studied with the aim to rationally identify and discuss the critical points in the nanoMIP-assay development, in an example based on the iron homeostasis biomarker hepcidin and hepcidin-specific nanoMIPs (Kd = 9nM). Plates were prepared by deposition and drying of nanoMIP (0...
February 1, 2018: Talanta
https://www.readbyqxmd.com/read/29114034/solution-structure-of-an-ultra-stable-single-chain-insulin-analog-connects-protein-dynamics-to-a-novel-mechanism-of-receptor-binding
#9
Michael D Glidden, Yanwu Yang, Nicholas A Smith, Nelson B Phillips, Kelley Carr, Nalinda P Wickramasinghe, Faramarz Ismail-Beigi, Michael C Lawrence, Brian J Smith, Michael A Weiss
Domain-minimized insulin receptors (IRs) have enabled crystallographic analysis of insulin-bound "micro-receptors." In such structures the C-terminal segment of the insulin B chain inserts between conserved IR domains, unmasking an invariant receptor-binding surface that spans both insulin A- and B chains. This "open" conformation not only rationalizes the inactivity of single-chain insulin (SCI) analogs (in which the A and B chains are directly linked), but also suggests that connecting (C) domains of sufficient length will bind the IR...
November 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29113893/saccharide-binding-by-intelectins
#10
Shailza Sharma, T N C Ramya
This communication probes ligand binding by human Intelectin-1 with several saccharides. Human Intelectin-1 was previously reported to bind to microbial glycans via ribofuranoside or galactofuranoside residues, whereas subsequently, a crystal structure of ligand bound hITLN1 indicated that hITLN1 does not bind to ribofuranoside but distinguishes between microbial and human glycans through a glycan motif - a terminal, acyclic 1,2-diol, which is present on galactofuranose and other microbial saccharides. Here, we demonstrate that besides glycerol and glycerol derivatives (which have an acyclic 1,2-diol), and 2-deoxy-d-galactose, d-ribose and 2-deoxy-d-ribose, which have been previously reported as human Intelectin-1 ligands, 2-C-hydroxymethyl-d-ribose, d-talose, d-idose, d-altrose and sorbitol also elute human Intelectin-1 from Sepharose CL-6B...
November 4, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29112372/tuning-the-color-palette-of-fluorescent-copper-sensors-through-systematic-heteroatom-substitution-at-rhodol-cores
#11
Shang Jia, Karla M Ramos-Torres, Safacan Kolemen, Cheri M Ackerman, Christopher J Chang
Copper is an essential nutrient for sustaining life, and emerging data have expanded the roles of this metal in biology from its canonical functions as a static enzyme cofactor to dynamic functions as a transition metal signal. At the same time, loosely bound, labile copper pools can trigger oxidative stress and damaging events that are detrimental if misregulated. The signal/stress dichotomy of copper motivates the development of new chemical tools to study its spatial and temporal distributions in native biological contexts such as living cells...
November 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29111717/discovery-of-a-novel-and-selective-indoleamine-2-3-dioxygenase-ido-1-inhibitor-3-5-fluoro-1h-indol-3-yl-pyrrolidine-2-5-dione-eos200271-pf-06840003-and-its-characterization-as-a-potential-clinical-candidate
#12
Stefano Crosignani, Patrick Bingham, Pauline Bottemanne, Hélène Cannelle, Sandra Cauwenberghs, Marie Cordonnier, Deepak Dalvie, Frederik Deroose, Jun Li Feng, Bruno Gomes, Samantha Greasley, Stephen E Kaiser, Manfred Kraus, Michel Négrerie, Karen A Maegley, Nichol Miller, Brion W Murray, Manfred Schneider, James Solowiej, Albert E Stewart, Joseph Tumang, Vince R Torti, Benoit Van den Eynde, Martin Wythes
Tumors use tryptophan-catabolizing enzymes such as Indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. SAR around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode...
November 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29111118/hsp90-and-thioredoxin-thioredoxin-reductase-enable-the-catalytic-activity-of-clostridial-neurotoxins-inside-nerve-terminals
#13
Marco Pirazzini, Domenico Azarnia Tehran, Giulia Zanetti, Ornella Rossetto, Cesare Montecucco
Botulinum (BoNTs) and tetanus (TeNT) neurotoxins are the most toxic substances known and form the growing family of Clostridial neurotoxins (CNT), the etiologic agents of botulism and tetanus. CNT are composed of a metalloprotease light chain (L), linked via a disulfide bond to a heavy chain (H). H mediates the binding to nerve terminals and the membrane translocation of L into the cytosol, where its substrates, the three SNARE proteins, are localized. L translocation is accompanied by unfolding and, once delivered on the cytosolic side of the endosome membrane, it has to be reduced and reacquire the native fold to be active...
October 27, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/29090436/interaction-between-enterprises-and-consumers-in-a-market-of-carbon-labeled-products-a-game-theoretical-analysis
#14
Rui Zhao, Jiaojie Han, Shaozhuo Zhong, Ya Huang
This paper applies an evolutionary game theoretical analysis combined with system dynamics to model strategic interaction between enterprises and consumers with bounded rationality in a carbon-labeled product market. Through the game theoretical analysis, possible equilibriums are predicted between these two players, in order to provide market recommendations for promotion of carbon-labeled products. The simulation results indicated that it is impossible to promote the carbon-labeled products relying on the market's inherent functions...
October 31, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29061513/rational-designing-of-an-antidote-nanoparticle-decorated-with-abiotic-polymer-ligands-for-capturing-and-neutralizing-target-toxins
#15
Hiroyuki Koide, Hiroki Tsuchida, Masahiko Nakamoto, Anna Okishima, Saki Ariizumi, Chiaki Kiyokawa, Tomohiro Asai, Yu Hoshino, Naoto Oku
Many of macromolecular toxins induce cell death by directly interacting with cells or induction of inflammatory cytokines. Abiotic polymer ligands (PLs) composed of functional monomers are able to bind and neutralize toxins in vivo and are of great interest for efficient antidotes. However, little has been reported about recognition and neutralization of target molecules in the bloodstream because of readily elimination from the bloodstream. Here, we report a rational design of PLs-decorated lipid nanoparticles (PL-NPs) for neutralizing a target toxin in vivo...
October 20, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29058876/synthetic-xylosides-probing-the-glycosaminoglycan-biosynthetic-machinery-for-biomedical-applications
#16
Jie Shi Chua, Balagurunathan Kuberan
Glycosaminoglycans (GAGs) are polysaccharides ubiquitously found on cell surfaces and in the extracellular matrix (ECM). They regulate numerous cellular signaling events involved in many developmental and pathophysiological processes. GAGs are composed of complex sequences of repeating disaccharide units, each of which can carry many different modifications. The tremendous structural variations account for their ability to bind many proteins and thus, for their numerous functions. Although the sequence of GAG biosynthetic events and the enzymes involved mostly were deduced a decade ago, the emergence of tissue or cell specific GAGs from a nontemplate driven process remains an enigma...
October 23, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29058712/molecular-basis-of-lipid-linked-oligosaccharide-recognition-and-processing-by-bacterial-oligosaccharyltransferase
#17
Maja Napiórkowska, Jérémy Boilevin, Tina Sovdat, Tamis Darbre, Jean-Louis Reymond, Markus Aebi, Kaspar P Locher
Oligosaccharyltransferase (OST) is a membrane-integral enzyme that catalyzes the transfer of glycans from lipid-linked oligosaccharides (LLOs) onto asparagine side chains, the first step in protein N-glycosylation. Here, we report the X-ray structure of a single-subunit OST, PglB from Campylobacter lari, trapped in an intermediate state bound to an acceptor peptide and a synthetic LLO analog. The structure reveals the role of the external loop EL5, present in all OST enzymes, in substrate recognition. Whereas the N-terminal half of EL5 binds LLO, the C-terminal half interacts with the acceptor peptide...
October 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29051736/novel-peripherally-restricted-cannabinoid-1-receptor-selective-antagonist-txx-522-with-prominent-weight-loss-efficacy-in-diet-induced-obese-mice
#18
Wei Chen, Fengchun Shui, Cheng Liu, Xinbo Zhou, Wei Li, Zhibing Zheng, Wei Fu, Lili Wang
The clinical development of the first generation of globally active cannabinoid 1 receptor (CB1R) antagonists was suspended because of their adverse neuropsychiatric effects. Selective blockade of peripheral CB1Rs has the potential to provide a viable strategy for the treatment of severe obesity while avoiding these central nervous system side effects. In the current study, a novel compound (TXX-522) was rationally designed based on the parent nucleus of a classical CB1R-selective antagonist/inverse agonist, rimonabant (SR141716A)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29051530/characterization-of-a-dual-function-macrocyclase-enables-design-and-use-of-efficient-macrocyclization-substrates
#19
Clarissa M Czekster, Hannes Ludewig, Stephen A McMahon, James H Naismith
Peptide macrocycles are promising therapeutic molecules because they are protease resistant, structurally rigid, membrane permeable, and capable of modulating protein-protein interactions. Here, we report the characterization of the dual function macrocyclase-peptidase enzyme involved in the biosynthesis of the highly toxic amanitin toxin family of macrocycles. The enzyme first removes 10 residues from the N-terminus of a 35-residue substrate. Conformational trapping of the 25 amino-acid peptide forces the enzyme to release this intermediate rather than proceed to macrocyclization...
October 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29038479/probing-ligand-recognition-of-the-opioid-pan-antagonist-at-076-at-nociceptin-kappa-mu-and-delta-opioid-receptors-through-structure-activity-relationships
#20
V Blair Journigan, Willma E Polgar, Edward W Tuan, James Lu, Pankaj R Daga, Nurulain T Zaveri
Few opioid ligands binding to the three classic opioid receptor subtypes, mu, kappa and delta, have high affinity at the fourth opioid receptor, the nociceptin/orphanin FQ receptor (NOP). We recently reported the discovery of AT-076 (1), (R)-7-hydroxy-N-((S)-1-(4-(3-hydroxyphenyl)piperidin-1-yl)-3-methylbutan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, a pan antagonist with nanomolar affinity for all four subtypes. Since AT-076 binds with high affinity at all four subtypes, we conducted a structure-activity relationship (SAR) study to probe ligand recognition features important for pan opioid receptor activity, using chemical modifications of key pharmacophoric groups...
October 16, 2017: Scientific Reports
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