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Molecular receptor affinity

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https://www.readbyqxmd.com/read/28919415/biophysical-characterization-of-the-interaction-between-heme-and-proteins-responsible-for-heme-transfer-in-streptococcus-pyogenes
#1
Masato Hoshino, Makoto Nakakido, Satoru Nagatoishi, Chihiro Aikawa, Ichiro Nakagawa, Kouhei Tsumoto
Streptococcus pyogenes, an important pathogen that causes a wide range of diseases, possesses the sia gene cluster, which encodes proteins involved in the heme acquisition system. Although this system was previously described, the molecular mechanism of effective heme transfer remains to be elucidated. Here, we have characterized the interactions between heme and each domain of Streptococcal hemoprotein receptor (Shr) and Streptococcal heme-binding protein (Shp). Our kinetic and thermodynamic analyses suggested that effective heme transfer within this system is achieved not only by affinity-based transfer but also by the difference of the binding driving force...
September 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28918196/expression-and-purification-of-human-and-saccharomyces-cerevisiae-equilibrative-nucleoside-transporters
#2
Rebba C Boswell-Casteel, Jennifer M Johnson, Zygy Roe-Žurž, Kelli D Duggan, Hannah Schmitz, Franklin A Hays
Nucleosides play an essential role in the physiology of eukaryotes by acting as metabolic precursors in de novo nucleic acid synthesis and energy metabolism. Nucleosides also act as ligands for purinergic receptors. Equilibrative nucleoside transporters (ENTs) are polytopic integral membrane proteins that aid in regulating plasmalemmal flux of purine and pyrimidine nucleosides and nucleobases. ENTs exhibit broad substrate selectivity across different isoforms and utilize diverse mechanisms to drive substrate flux across membranes...
September 13, 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28916358/the-functional-characterization-and-comparison-of-two-single-crd-containing-c-type-lectins-with-novel-and-typical-key-motifs-from-portunus-trituberculatus
#3
Mengmeng Huang, Changkao Mu, Yuehong Wu, Fei Ye, Dan Wang, Cong Sun, Zhengbing Lv, Bingnan Han, Chunlin Wang, Xue-Wei Xu
C-type lectins are a superfamily of Ca(2+)-dependent carbohydrate-recognition proteins, which play crucial roles in innate immunity including nonself-recognition and pathogen elimination. In the present study, two single-CRD containing C-type lectins were identified from swimming crab Portunus trituberculatus (designated as PtCTL-2 and PtCTL-3). The open reading frame (ORF) of PtCTL-2 encoded polypeptides of 485 amino acids with a signal peptide and a single carbohydrate-recognition domain (CRD), while PtCTL-3's ORF encoded polypeptides of 241 amino acids with a coiled-coil region and a single-CRD...
September 12, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28915592/targeted-alpha-therapy-using-a-novel-cd70-targeted-thorium-227-conjugate-in-in-vitro-and-in-vivo-models-of-renal-cell-carcinoma
#4
Urs B Hagemann, Dessislava Mihaylova, Steinar R Uran, Joergen Borrebaek, Derek Grant, Roger M Bjerke, Jenny Karlsson, Alan S Cuthbertson
The cell surface receptor CD70 has been previously reported as a promising target for B-cell lymphomas and several solid cancers including renal cell carcinoma. We describe herein the characterization and efficacy of a novel CD70 targeted thorium-227 conjugate (CD70-TTC) comprising the combination of the three components, a CD70 targeting antibody, a chelator moiety and the short-range, high-energy alpha-emitting radionuclide thorium-227 ((227)Th). In vitro analysis demonstrated that the CD70-TTC retained binding affinity to its target and displayed potent and specific cytotoxicity compared to an isotype control-TTC...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28913743/predicting-the-affinity-of-farnesoid-x-receptor-ligands-through-a-hierarchical-ranking-protocol-a-d3r-grand-challenge-2-case-study
#5
Manon Réau, Florent Langenfeld, Jean-François Zagury, Matthieu Montes
The Drug Design Data Resource (D3R) Grand Challenges are blind contests organized to assess the state-of-the-art methods accuracy in predicting binding modes and relative binding free energies of experimentally validated ligands for a given target. The second stage of the D3R Grand Challenge 2 (GC2) was focused on ranking 102 compounds according to their predicted affinity for Farnesoid X Receptor. In this task, our workflow was ranked 5th out of the 77 submissions in the structure-based category. Our strategy consisted in (1) a combination of molecular docking using AutoDock 4...
September 14, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28911813/functional-dynamics-in-cyclic-nucleotide-signaling-and-amyloid-inhibition
#6
REVIEW
Bryan VanSchouwen, Rashik Ahmed, Julijana Milojevic, Giuseppe Melacini
It is now established that understanding the molecular basis of biological function requires atomic resolution maps of both structure and dynamics. Here, we review several illustrative examples of functional dynamics selected from our work on cyclic nucleotide signaling and amyloid inhibition. Although fundamentally diverse, a central aspect common to both fields is that function can only be rationalized by considering dynamic equilibria between distinct states of the accessible free energy landscape. The dynamic exchange between ground and excited states of signaling proteins is essential to explain auto-inhibition and allosteric activation...
September 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28900792/relative-binding-affinity-prediction-of-farnesoid-x-receptor-in-the-d3r-grand-challenge-2-using-fep
#7
Christina Schindler, Friedrich Rippmann, Daniel Kuhn
Physics-based free energy simulations have increasingly become an important tool for predicting binding affinity and the recent introduction of automated protocols has also paved the way towards a more widespread use in the pharmaceutical industry. The D3R 2016 Grand Challenge 2 provided an opportunity to blindly test the commercial free energy calculation protocol FEP+ and assess its performance relative to other affinity prediction methods. The present D3R free energy prediction challenge was built around two experimental data sets involving inhibitors of farnesoid X receptor (FXR) which is a promising anticancer drug target...
September 12, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28899696/serotonin-2a-receptor-disulfide-bridge-integrity-is-crucial-for-ligand-binding-to-different-signalling-states-but-not-for-its-homodimerization
#8
Alba Iglesias, Marta Cimadevila, Rocío Ailim de la Fuente, María Martí-Solano, María Isabel Cadavid, Marián Castro, Jana Selent, María Isabel Loza, José Brea
The serotonin 2A (5-HT2A) receptor is a G-protein coupled receptor (GPCR) with a conserved disulfide bridge formed by Cys(148) (transmembrane helix 3, TM3) and Cys(227) (extracellular loop 2, ECL-2). We hypothesized that disulfide bridges may determine serotonin 5-HT2A receptor functions such as receptor activation, functional selectivity and ligand recognition. We used the reducing agent dithiothreitol (DTT) to determine how the reduction of disulfide bridges affects radioligand binding, second messenger mobilization and receptor dimerization...
September 9, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28898517/characterization-of-the-functional-activity-of-botulinum-neurotoxin-subtype-b6
#9
Tomoko Kohda, Keiji Nakamura, Koji Hosomi, Yasushi Torii, Shunji Kozaki, Masafumi Mukamoto
Clostridium botulinum produces the highly potent neurotoxin, botulinum neurotoxin (BoNT), which is classified into seven serotypes, A-G, and the subtype classification is confirmed by the diversity of the amino acid sequence among the serotypes. The BoNT from the Osaka05 strain is associated with type B infant botulism and has been divided into BoNT/B subtype B6 (BoNT/B6) by phylogenetic analysis and the antigenicity of its C-terminal heavy chain (HC) domain. However, the molecular basis for its properties, including the potency, is poorly understood...
September 12, 2017: Microbiology and Immunology
https://www.readbyqxmd.com/read/28895785/preclinical-pharmacokinetic-characterization-of-an-adipose-tissue-targeting-monoclonal-antibody-in-obese-and-non-obese-animals
#10
Sharmila Rajan, Danielle Mandikian, Amos Baruch, Thomas R Gelzleichter, Dale Stevens, Junichiro Sonoda, Kyra Cowan, C Andrew Boswell, Eric Stefanich
Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and βKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/βKlotho...
September 12, 2017: MAbs
https://www.readbyqxmd.com/read/28893570/phytoestrogenic-effect-of-inula-racemosa-hook-f-a-cardioprotective-root-drug-in-traditional-medicine
#11
Mangathayaru Kalachaveedu, Divya Raghavan, Srivani Telapolu, Sarah Kuruvilla, Balakrishna Kedike
ETHNOPHARMACOLOGICAL RELEVANCE: Roots of Inula racemosa are used as a cardio protective in Ayurveda in India, being prescribed as a medicine for precordial chest pain, cough and dyspnoea, both singly and as a poly herbal. AIM: Evaluation of Phytoestrogenic activity of the root extracts of Inula racemosa and compounds isolated therefrom in vivo, in silico and in vitro. MATERIALS AND METHODS: Alcohol (IrA) and hexane (IrH) extracts characterized by HPTLC/GC-MS analysis respectively and processed for compound isolation were evaluated for estrogenic activity (100 & 250mg/kg bw) by the Immature rat uterotrophic assay using ethinylestradiol (EE -30µg/kg bw) as standard drug...
September 8, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28893136/investigation-on-the-binding-mechanism-of-loratinib-with-the-c-ros-oncogene-1-ros1-receptor-tyrosine-kinase-via-molecular-dynamics-simulation-and-binding-free-energy-calculations
#12
XiaoYun Wu, YuanYuan Wang, ShanHe Wan, JiaJie Zhang
The c-ros oncogene 1 (ROS1) has proven to be an important cancer target for the treatment of various human cancers. The anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been granted approval for the treatment of patients with ROS1 positive metastatic non-small-cell lung cancer (NSCLC) by the Food and Drug Administration (FDA) on 2016. However, serious resistance due to the secondary mutation of glycine 2032 to arginine (G2032R) was developed in clinical studies. Loratinib (PF-06463922), a macrocyclic analogue of crizotinib, showed significantly improved inhibitory activity against wild-type (WT) ROS1 and ROS1(G2032R) mutant...
September 11, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28889350/binding-free-energy-predictions-of-farnesoid-x-receptor-fxr-agonists-using-a-linear-interaction-energy-lie-approach-with-reliability-estimation-application-to-the-d3r-grand-challenge-2
#13
Eko Aditya Rifai, Marc van Dijk, Nico P E Vermeulen, Daan P Geerke
Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds...
September 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28888944/the-novel-dopamine-d3-receptor-antagonists-partial-agonists-cab2-015-and-bak4-54-inhibit-oxycodone-taking-and-oxycodone-seeking-behavior-in-rats
#14
Zhi-Bing You, Jun-Tao Gao, Guo-Hua Bi, Yi He, Comfort Boateng, Jianjing Cao, Eliot L Gardner, Amy Hauck Newman, Zheng-Xiong Xi
The use of prescription opioid analgesics, particularly oxycodone, has dramatically increased, and parallels escalated opioid abuse and drug-related deaths worldwide. Understanding the molecular mechanisms underlying the development of opioid dependence and expanding treatment options to counter prescription opioid abuse has become a critical public health matter. In the present study, we first evaluated the reinforcing effects of oxycodone in a rat model of self-administration and then explored the potential utility of two novel high affinity dopamine D3 receptor (D3R) antagonists/partial agonists, CAB2-015 and BAK4-54, for treatment of prescription opioid abuse and dependence...
September 6, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28884163/identification-of-a-novel-class-of-brd4-inhibitors-by-computational-screening-and-binding-simulations
#15
Bryce K Allen, Saurabh Mehta, Stuart W J Ember, Jin-Yi Zhu, Ernst Schönbrunn, Nagi G Ayad, Stephan C Schürer
Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank...
August 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/28883627/development-of-fluorescent-probes-that-target-serotonin-5-ht2b-receptors
#16
Jhonny Azuaje, Paula López, Alba Iglesias, Rocío A de la Fuente, José M Pérez-Rubio, Diego García, Tomasz Maciej Stępniewski, Xerardo García-Mera, José M Brea, Jana Selent, Dolores Pérez, Marián Castro, María I Loza, Eddy Sotelo
Some 5-HT2B fluorescent probes were obtained by tagging 1-(2,5-dimethoxy-4-iodophenyl)-propan-2-amine (DOI) with a subset of fluorescent amines. Some of the resulting fluorescent ligands showed excellent affinity and selectivity profiles at the 5-HT2B receptors (e.g. 12b), while retain the agonistic functional behaviour of the model ligand (DOI). The study highlighted the most salient features of the structure-activity relationship in this series and these were substantiated by a molecular modelling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human 5-HT2B receptor...
September 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28882502/design-and-synthesis-of-benzoacridines-as-estrogenic-and-anti-estrogenic-agents
#17
Kohei Torikai, Rintaro Koga, Xiaohui Liu, Kaoru Umehara, Tatsuya Kitano, Kenji Watanabe, Tohru Oishi, Hiroshi Noguchi, Yasuyuki Shimohigashi
Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents...
August 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28876351/optimization-of-a-synthetic-receptor-for-dimethyllysine-using-a-biphenyl-2-6-dicarboxylic-acid-scaffold-insights-into-selective-recognition-of-hydrophilic-guests-in-water
#18
Isaiah N Gober, Marcey L Waters
In the design of small molecule receptors for polar guests, much inspiration has been taken from proteins that have adapted effective ways to selectively bind polar molecules in aqueous environments. Nonetheless, molecular recognition of hydrophilic guests in water by synthetic receptors remains a challenging task. Here we report a new synthetic receptor, A2I, with improved affinity and selectivity for a biologically important polar guest, dimethyllysine (Kme2). A2I was prepared via redesign of a small molecule receptor (A2B) that preferentially binds trimethyllysine (Kme3) using dynamic combinatorial chemistry (DCC)...
September 6, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28872302/high-affinity-interactions-of-beryllium-2-with-phosphatidylserine-result-in-a-cross-linking-effect-reducing-surface-recognition-of-the-lipid
#19
Yuri Ermakov, Kishore Kamaraju, Antonina Dunina-Barkovskaya, Khava S Vishnyakova, Yegor E Yegorov, Andriy Anishkin, Sergei Sukharev
Beryllium has multiple industrial applications, but its manufacture is associated with serious occupational risk of developing chronic inflammation in lungs known as berylliosis, or chronic beryllium disease (CBD). Although the Be2+-induced abnormal immune responses have recently been linked to a specific MHCII allele, the nature of long-lasting granulomas is not fully understood. Here we show that Be2+ binds with a micromolar affinity to phosphatidylserine (PS), the major surface marker of apoptotic cells...
September 5, 2017: Biochemistry
https://www.readbyqxmd.com/read/28869862/bmp-2-and-bmp-9-binding-specificities-with-alk-3-in-aqueous-solution-with-dynamics
#20
Orkid Coskuner, Vladimir N Uversky
Signal ligands of the transforming growth factor-β (TGF-β) superfamily include the bone morphogenetic proteins (BMPs). BMPs bind to type I and type II serine-threonine kinase receptors and trigger the transphosphorylation cascade, wherein the active type II receptor phosphorylates the inactive type I receptor. This process further activates the cytoplasmic effectors of the pathway, such as SMAD proteins, which are homologs of both the Drosophila protein MAD (mothers against decapentaplegic) and the Caenorhabditis elegans protein SMA (small body size)...
August 9, 2017: Journal of Molecular Graphics & Modelling
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