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Molecular receptor affinity

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https://www.readbyqxmd.com/read/28645833/binding-kinetics-and-pathways-of-ligands-to-gpcrs
#1
REVIEW
Andrea Strasser, Hans-Joachim Wittmann, Roland Seifert
Previously, drugs were developed focusing on target affinity and selectivity. However, it is becoming evident that the drug-target residence time, related to the off-rate, is an important parameter for successful drug development. The residence time influences both the on-rate and overall effectiveness of drugs. Furthermore, ligand binding is now appreciated to be a multistep process because metastable and/or intermediate binding sites in the extracellular region have been identified. In this review, we summarize experimental ligand-binding data for G-protein-coupled receptors (GPCRs), and their binding pathways, analyzed by molecular dynamics (MD)...
June 20, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28639323/molecular-interactions-of-dioxins-and-dlcs-with-the-xenosensors-pxr-and-car-an-in-silico-risk-assessment-approach
#2
Garima Verma, Mohemmed Faraz Khan, Mohammad Shaquiquzzaman, Wasim Akhtar, Mymoona Akhter, Syed Misbahul Hasan, Mohammad Mumtaz Alam
Dioxins and dioxin-like compounds (DLCs) are known to cause endocrine disruption in humans and animals. Being lipophilic xenobiotic chemicals, they can be easily absorbed into the biological system from the surrounding environments, thereby causing various health dysfunctions. In the present study, a total of 100 dioxins and DLCs were taken, and their binding pattern was assessed with the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in comparison with the corresponding known inhibitors and a well-studied endocrine disrupting xenobiotic, bisphenol A (BPA)...
June 22, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28636281/aryl-and-heteroaryl-substituted-phenylalanines-as-ampa-receptor-ligands
#3
Ewa Szymańska, Paulina Chałupnik, Tommy N Johansen, Birgitte Nielsen, Ana Maria Cuñado Moral, Darryl S Pickering, Anna Więckowska, Katarzyna Kieć-Kononowicz
A series of racemic unnatural amino acids was rationally designed on the basis of recently published X-ray structures of the GluA2 LBD with bound phenylalanine-based antagonists. Twelve new diaryl- or aryl/heteroaryl-substituted phenylalanine derivatives were synthesized and evaluated in vitro in radioligand binding assays at native rat ionotropic glutamate receptors. The most interesting compound in this series, (RS)-2-amino-3-(3'-hydroxy-5-(1H-pyrazol-4-yl)-[1,1'-biphenyl]-3-yl)propanoic acid 7e, showed the binding affinity of 4...
June 21, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28632753/mait-cells-launch-a-rapid-robust-and-distinct-hyperinflammatory-response-to-bacterial-superantigens-and-quickly-acquire-an-anergic-phenotype-that-impedes-their-cognate-antimicrobial-function-defining-a-novel-mechanism-of-superantigen-induced-immunopathology
#4
Christopher R Shaler, Joshua Choi, Patrick T Rudak, Arash Memarnejadian, Peter A Szabo, Mauro E Tun-Abraham, Jamie Rossjohn, Alexandra J Corbett, James McCluskey, John K McCormick, Olivier Lantz, Roberto Hernandez-Alejandro, S M Mansour Haeryfar
Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections...
June 2017: PLoS Biology
https://www.readbyqxmd.com/read/28632381/molecular-modeling-of-the-interactions-between-carborane-containing-analogs-of-indomethacin-and-cyclooxygenase-2
#5
Menyhárt-Botond Sárosi, Wilma Neumann, Terry P Lybrand, Evamarie Hey-Hawkins
Molecular modeling studies were performed in order to gain insight into the binding mode and interaction of carborane-containing derivatives of indomethacin methyl ester with the cyclooxygenase 2 (COX 2) isoform, and to assess the predictive capability of the computational tools available for studying carboranes, a unique class of pharmacophores. Docking simulations were able to identify the correct binding mode and reproduced the experimental binding affinity trends with encouraging quality. Nevertheless, the docking results needed to be verified through extensive and resource intensive quantum chemical calculations, and the interpretation of the theoretical results would not have been straightforward without the supporting experimental data...
June 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28632177/the-intersection-of-ngf-trka-signaling-and-amyloid-precursor-protein-processing-in-alzheimer-s-disease-neuropathology
#6
REVIEW
Nadia Canu, Giuseppina Amadoro, Viviana Triaca, Valentina Latina, Valentina Sposato, Veronica Corsetti, Cinzia Severini, Maria Teresa Ciotti, Pietro Calissano
Dysfunction of nerve growth factor (NGF) and its high-affinity Tropomyosin receptor kinase A (TrkA) receptor has been suggested to contribute to the selective degeneration of basal forebrain cholinergic neurons (BFCN) associated with the progressive cognitive decline in Alzheimer's disease (AD). The aim of this review is to describe our progress in elucidating the molecular mechanisms underlying the dynamic interplay between NGF/TrkA signaling and amyloid precursor protein (APP) metabolism within the context of AD neuropathology...
June 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28630016/comparative-transcriptome-analysis-of-sinonovacula-constricta-in-gills-and-hepatopancreas-in-response-to-vibrio-parahaemolyticus-infection
#7
Xuelin Zhao, Xuemei Duan, Zhenhui Wang, Weiwei Zhang, Ye Li, Chunhua Jin, Jinbo Xiong, Chenghua Li
The razor clam Sinonovacula constricta is an important economic species in China. However, bacterial pathogenic diseases limits S. constricta farming industry for large-scale production. In this study, de novo transcriptome sequencing was performed on S. constricta gills and hepatopancreas under Vibrio parahaemolyticus challenge for 12 h and 48 h, respectively. Transcripts assembly constructed 18,330 sequences, each of which was 500 bp long and functionally annotated, and 1781 and 490 transcripts were differentially expressed in the gills and hepatopancreas, respectively...
June 16, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28623230/flexible-body-motions-of-calmodulin-and-the-farnesylated-hypervariable-region-yield-a-high-affinity-interaction-enabling-k-ras4b-membrane-extraction
#8
Hyunbum Jang, Avik Banerjee, Tanmay Chavan, Vadim Gaponenko, Ruth Nussinov
In calmodulin (CaM)-rich environments, oncogenic KRAS plays a critical role in adenocarcinomas by promoting PI3K/Akt signaling. We previously proposed that at elevated calcium levels in cancer, CaM recruits PI3Kα to the membrane and extracts K-Ras4B from the membrane, organizing a K-Ras4B/CaM/PI3Kα ternary complex. CaM can thereby replace a missing receptor tyrosine kinase signal to fully activate PI3Kα. Recent experimental data show that CaM selectively promotes K-Ras signaling, but not of N-Ras or H-Ras...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28622647/endocrine-disrupting-activity-of-per-and-polyfluoroalkyl-substances-exploring-combined-approaches-of-ligand-and-structure-based-modeling
#9
Supratik Kar, Maria S Sepúlveda, Kunal Roy, Jerzy Leszczynski
Exposure to perfluorinated and polyfluoroalkyl substances (PFCs/PFASs), endocrine disrupting halogenated pollutants, has been linked to various diseases including thyroid toxicity in human populations across the globe. PFASs can compete with thyroxine (T4) for binding to the human thyroid hormone transport protein transthyretin (TTR) which may lead to reduce thyroid hormone levels leading to endocrine disrupting adverse effects. Environmental fate and endocrine-disrupting activity of PFASs has initiated several research projects, but the amount of experimental data available for these pollutants is limited...
June 9, 2017: Chemosphere
https://www.readbyqxmd.com/read/28620761/medicinal-chemistry-of-%C3%AF-1-receptor-ligands-pharmacophore-models-synthesis-structure-affinity-relationships-and-pharmacological-applications
#10
Frauke Weber, Bernhard Wünsch
In the first part of this chapter, we summarize the various pharmacophore models for σ1 receptor ligands. Common to all of them is a basic amine flanked by two hydrophobic regions, representing the pharmacophoric elements. The development of computer-based models like the 3D homology model is described as well as the first crystal structure of the σ1 receptor. The second part focuses on the synthesis and biological properties of different σ1 receptor ligands, identified as 1-9. Monocyclic piperazines 1 and bicyclic piperazines 2 and 3 were developed as cytotoxic compounds, thus the IC50 values of cell growth and survival inhibition studies are given for all derivatives...
June 16, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28620721/a-novel-gain-of-function-mutation-in-the-itpr1-suppressor-domain-causes-spinocerebellar-ataxia-with-altered-ca-2-signal-patterns
#11
Jillian P Casey, Taisei Hirouchi, Chihiro Hisatsune, Bryan Lynch, Raymond Murphy, Aimee M Dunne, Akitoshi Miyamoto, Sean Ennis, Nick van der Spek, Bronagh O'Hici, Katsuhiko Mikoshiba, Sally Ann Lynch
We report three affected members, a mother and her two children, of a non-consanguineous Irish family who presented with a suspected autosomal dominant spinocerebellar ataxia characterized by early motor delay, poor coordination, gait ataxia, and dysarthria. Whole exome sequencing identified a novel missense variant (c.106C>T; p.[Arg36Cys]) in the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor gene (ITPR1) as the cause of the disorder, resulting in a molecular diagnosis of spinocerebellar ataxia type 29...
June 15, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28620365/metabolic-value-chemoattractants-are-preferentially-recognized-at-broad-ligand-range-chemoreceptor-of-pseudomonas-putida-kt2440
#12
Matilde Fernández, Miguel A Matilla, Álvaro Ortega, Tino Krell
Bacteria have evolved a wide range of chemoreceptors with different ligand specificities. Typically, chemoreceptors bind ligands with elevated specificity and ligands serve as growth substrates. However, there is a chemoreceptor family that has a broad ligand specificity including many compounds that are not of metabolic value. To advance the understanding of this family, we have used the PcaY_PP (PP2643) chemoreceptor of Pseudomonas putida KT2440 as a model. Using Isothermal Titration Calorimetry we showed here that the recombinant ligand binding domain (LBD) of PcaY_PP recognizes 17 different C6-ring containing carboxylic acids with KD values between 3...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28620157/a-novel-cell-membrane-affinity-sample-pretreatment-technique-for-recognition-and-preconcentration-of-active-components-from-traditional-chinese-medicine
#13
Yusi Bu, Xiaoshuang He, Qi Hu, Cheng Wang, Xiaoyu Xie, Sicen Wang
We describe a novel biomembrane affinity sample pretreatment technique to quickly screen and preconcentrate active components from traditional Chinese medicine (TCM), which adopts cell membrane coated silica particles (CMCSPs) as affinity ligands which benefit the biomembrane's ability to maximize simulation of drug-receptor interactions in vivo. In this study, the prepared CMCSPs formed by irreversible adsorption of fibroblast growth factor receptor 4 (FGFR4) cell membrane on the surface of silica were characterized using different spectroscopic and imaging instruments...
June 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28619479/a-demonstration-of-analytical-similarity-comparing-a-proposed-biosimilar-pegfilgrastim-and-reference-pegfilgrastim
#14
Stephen Brokx, Louise Scrocchi, Nirmesh Shah, Jason Dowd
BACKGROUND: Recombinant human granulocyte-colony stimulating factor (G-CSF, filgrastim) is used primarily to reduce incidence and duration of severe neutropenia and its associated complications in cancer patients that have received a chemotherapy regimen. The pegylated form of filgrastim, "pegfilgrastim", is a long-acting form that requires only a once-per-cycle administration for the management of chemotherapy-induced neutropenia. Apobiologix, a division of ApoPharma USA, Inc., and Intas Pharmaceuticals Limited have co-developed a proposed pegfilgrastim biosimilar to US-licensed pegfilgrastim...
June 12, 2017: Biologicals: Journal of the International Association of Biological Standardization
https://www.readbyqxmd.com/read/28618966/-68-ga-177-lu-labeled-dota-tate-shows-similar-imaging-and-biodistribution-in-neuroendocrine-tumor-model
#15
Fei Liu, Hua Zhu, Jiangyuan Yu, Xuedi Han, Qinghua Xie, Teli Liu, Chuanqin Xia, Nan Li, Zhi Yang
Somatostatin receptors are overexpressed in neuroendocrine tumors, whose endogenous ligands are somatostatin. DOTA-TATE is an analogue of somatostatin, which shows high binding affinity to somatostatin receptors. We aim to evaluate the (68)Ga/(177)Lu-labeling DOTA-TATE kit in neuroendocrine tumor model for molecular imaging and to try human-positron emission tomography/computed tomography imaging of (68)Ga-DOTA-TATE in neuroendocrine tumor patients. DOTA-TATE kits were formulated and radiolabeled with (68)Ga/(177)Lu for (68)Ga/(177)Lu-DOTA-TATE (M-DOTA-TATE)...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28614667/n-glycosylation-of-asparagine-130-in-the-extracellular-domain-of-the-human-calcitonin-receptor-significantly-increases-peptide-hormone-affinity
#16
Sang-Min Lee, Jason M Booe, Joseph J Gingell, Virginie Sjoelund, Debbie L Hay, Augen A Pioszak
The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is activated by the peptide hormones calcitonin and amylin. Calcitonin regulates bone remodeling through CTR, whereas amylin regulates blood glucose and food intake by activating CTR in complex with receptor activity-modifying proteins (RAMPs). These receptors are targeted clinically for the treatment of osteoporosis and diabetes. Here, we define the role of CTR N-glycosylation in hormone binding using purified calcitonin and amylin receptor extracellular domain (ECD) glycoforms and fluorescence polarization/anisotropy and isothermal titration calorimetry peptide-binding assays...
June 26, 2017: Biochemistry
https://www.readbyqxmd.com/read/28609757/a-molecular-docking-study-of-the-interactions-between-human-transferrin-and-seven-metallocene-dichlorides
#17
Jorge R Güette-Fernández, Enrique Meléndez, Wilson Maldonado-Rojas, Carlos Ortega-Zúñiga, Jesus Olivero-Verbel, Elsie I Parés-Matos
Human Transferrin (hTf) is a metal-binding protein found in blood plasma and is well known for its role in iron delivery. With only a 30% of its capacity for Fe(+3) binding, this protein has the potential ability to transport other metal ions or organometallic compounds from the blood stream to all cell tissues. In this perspective, recent studies have described seven metallocene dichlorides (Cp2M(IV)Cl2, M(IV)=V, Mo, W, Nb, Ti, Zr, Hf) suitable as anticancer drugs and less secondary effects than cisplatin...
May 30, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28608961/high-affinity-click-rgd-peptidomimetics-as-radiolabeled-probes-for-imaging-%C3%AE-v%C3%AE-3-integrin
#18
Monica Piras, Andrea Testa, Ian N Fleming, Sergio Dall'Angelo, Alexandra Andriu, Sergio Menta, Mattia Mori, Gavin D Brown, Duncan Forster, Kaye J Williams, Matteo Zanda
Non-peptidic RGD-mimic ligands were designed and synthesized by click chemistry between an arginine-azide mimic and an aspartic acid-alkyne mimic. Some of these molecules combine excellent in vitro properties (high αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g. tritium and [18F]fluorine, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD-mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations...
June 13, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28608697/perspectives-of-cannabinoid-type-2-receptor-cb2r-ligands-in-neurodegenerative-disorders-structure-affinity-relationship-safir-and-structure-activity-relationship-sar-studies
#19
Francesco Spinelli, Elena Capparelli, Carmen Abate, Nicola A Colabufo, Marialessandra Contino
Up-regulation of CB2R on activated microglial cells, the first step in neurodegeneration, has been widely demonstrated, and this finding makes the receptor a promising target in the early diagnosis and treatment of several neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). The development of CB2R PET ligands could help demonstrate the neurodegenerative pathogenesis, thus providing useful tools for characterizing the role of neuroinflammation in the progression of these disorders...
June 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28607591/pet-of-her2-expression-with-a-novel-18-fal-labeled-affibody
#20
Yuping Xu, Zhicheng Bai, Qianhuan Huang, Yunyun Pan, Donghui Pan, Lizhen Wang, Junjie Yan, Xinyu Wang, Runlin Yang, Min Yang
Background: Human epidermal growth factor receptor type 2 (HER2) is abundant in a wide variety of tumors and associated with the poor prognosis. Radiolabeled affibodies are potential candidates for detecting HER2-positive lesions. However, laborious multiple-step synthetic procedure and high abdomen background may hinder the widespread use. Herein, cysteinylated ZHER2:342 modified with a new hydrophilic linker (denoted as MZHER2:342) was designed and labeled using (18)FAl-NOTA strategies. The biologic efficacy of the novel tracer and its feasibilities for in vivo monitoring HER2 levels were also investigated in xenograft models with different HER2 expressions...
2017: Journal of Cancer
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