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Molecular receptor affinity

Anders Lundgren, Björn Agnarsson, Ronald Zirbs, Vladimir P Zhdanov, Erik Reimhult, Fredrik Höök
Emerging biomedical applications such as molecular imaging and drug delivery often require directed binding of nanoparticles to cell-membrane receptors. The specific apparent affinity of such ligand-functionalized particles is size-dependent, an observation so far solely attributed to multivalent receptor-ligand interaction. We question the universality of this explanation by demonstrating that the binding kinetics also depends on weak, attractive colloidal-type interaction between nanoparticles and a lipid membrane...
October 26, 2016: ACS Nano
Berhane Ghebrehiwet, Allen P Kaplan, Kusumam Joseph, Ellinor I B Peerschke
The blood plasma contains four biologically important proteolytic cascades, which probably evolved from the same ancestral gene. This in part may explain why each cascade has very similar "initiating trigger" followed by sequential and cascade-like downstream enzymatic activation pattern. The four cascades are: the complement system, the blood clotting cascade, the fibrinolytic system, and the kallikrein-kinin system. Although much has been written about the interplay between all these enzymatic cascades, the cross-talk between the complement and the kinin generating systems has become particularly relevant as this interaction results in the generation of nascent molecules that have significant impact in various inflammatory diseases including angioedema and cancer...
November 2016: Immunological Reviews
Iva Bruhova, Anthony Auerbach
Acetylcholine (ACh) released at the vertebrate nerve-muscle synapse is hydrolyzed rapidly into choline (Cho), so endplate receptors (AChRs) are exposed to high concentrations of both of these structurally-related ligands. To understand how these receptors distinguish ACh and Cho, we used single-channel electrophysiology to measure resting affinities (binding free energies) of these and other agonists in adult-type mouse AChRs having a mutation(s) at the transmitter-binding sites. The aromatic rings of αY190, αW149 and αY198 each provide ∼50% less binding energy for Cho compared to ACh...
October 25, 2016: Journal of Physiology
Vasanthi Jayakumar, Shiek S S J Ahmed, Kesavarao Kumar Ebenezar
To investigate the effect of curcumin on the multivariate and docking analysis on peroxisome proliferator activated receptor-γ, the rats were fed with high fructose diet (Group 2) to induce insulin resistance and curcumin was co-administered orally (Group 4) for a period of 8 weeks and measured the biochemical parameters in blood, kidney and liver tissues. The results showed a significant (p ≤ 0.05) increase in the level of creatinine, glucose, insulin, low density lipoprotein, total cholesterol, triglyceride, urea, uric acid, very low density lipoprotein and decreased albumin, high density lipoprotein and total protein level in the blood of Group 2 when compared with Group 1 control rats...
2016: SpringerPlus
Rafael Conceição de Souza, Gabriela de Medeiros Muniz, Andrei Santos Siqueira, Adonis de Melo Lima, Alessandra Pereira da Silva, Evonnildo Costa Gonçalves, João Lídio da Silva Gonçalves Vianez Júnior
Human immunodeficiency virus (HIV) infections continue to exert an enormous impact on global human health. This led experts to emphasize the importance of new measures for preventing HIV infections, including the development of vaccines and novel drugs. In this context, a promising approach involves the use of lectins that can bind the surface envelope glycoprotein gp120 of HIV with high affinity, preventing viral entry. The cyanobacterial lectin microvirin (MVN) has been proposed as a candidate for development as a topical microbicide because of its ability to bind to high mannose-type glycans, potently inhibiting HIV-1 entry...
November 2016: Journal of Molecular Modeling
Jie Gao, Narasimha Midde, Jun Zhu, Alvin V Terry, Campbell McInnes, James M Chapman
Using molecular modeling and rationally designed structural modifications, the multi-target structure-activity relationship for a series of ranitidine analogs has been investigated. Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties provide optimal interactions with the hydrophobic and π-π interactions with the peripheral anionic site of the AChE active site. The SAR of a series of cyclic imides demonstrated that AChE inhibition is increased by additional aromatic rings, where 1,8-naphthalimide derivatives were the most potent analogs and other key determinants were revealed...
October 6, 2016: Bioorganic & Medicinal Chemistry Letters
Greg Hodge, Eugene Roscioli, Hubertus Jersmann, Hai B Tran, Mark Holmes, Paul N Reynolds, Sandra Hodge
BACKGROUND: Corticosteroid resistance is a major barrier to effective treatment of COPD. We have shown that the resistance is associated with decreased expression of glucocorticoid receptor (GCR) by senescent CD28nullCD8+ pro-inflammatory lymphocytes in peripheral blood of COPD patients. GCR must be bound to molecular chaperones heat shock proteins (Hsp) 70 and Hsp90 to acquire a high-affinity steroid binding conformation, and traffic to the nucleus. We hypothesized a loss of Hsp70/90 from these lymphocytes may further contribute to steroid resistance in COPD...
October 21, 2016: Respiratory Research
Xing-Hai Liu, Wen Zhao, Zhong-Hua Shen, Jia-Hua Xing, Tian-Ming Xu, Wei-Li Peng
A series of novel difluoromethylpyrazole carboxamides derivatives were synthesized by introduction of flexible alkyl chain. Nematicidal bioassay results showed that some of them exhibited good control efficacy against M. incognita, which indicated that these difluoromethylpyrazole carboxamides derivatives might be potential novel lead compounds for discovery new nematicides. The nematicidal activity was affected by the substituted position in the molecule, especially the substitution group on the alkyl chain...
October 10, 2016: European Journal of Medicinal Chemistry
Paul R Territo, Jill A Meyer, Jonathan S Peters, Amanda A Riley, Brian P McCarthy, Mingzhang Gao, Min Wang, Mark A Green, Qi-Huang Zheng, Gary D Hutchins
BACKGROUND: The P2X7 receptor represents a novel molecular target for imaging neuroinflammation via PET. GSK1482160, a potent P2X7 receptor antagonist, has high receptor affinity, blood-brain barrier penetration, and has been recently radiolabel ((11)C-GSK1482160). Therefore, we report the initial physical and biological characterization of this novel ligand. METHODS: (11)C-GSK1482160 synthesis was according to published methods. Cell density studies were performed in human embryonic kidney cell lines expressing human P2X7 receptors (HEK293-hP2X7R) and analyzed by western blot analysis, immuno-fluorescence assay (IFA), and radiologic-immunohistochemistry (RIHC) using P2X7R polyclonal antibodies...
October 20, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Ewa Szymańska, Paulina Chałupnik, Katarzyna Szczepańska, Ana Maria Cuñado Moral, Darryl S Pickering, Birgitte Nielsen, Tommy N Johansen, Katarzyna Kieć-Kononowicz
A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1-GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (Ki values in the range of 4.9-7.5μM). A structure-activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established...
September 30, 2016: Bioorganic & Medicinal Chemistry Letters
Shehla Akbar, Fazal Subhan, Nasiara Karim, Muhammad Shahid, Nisar Ahmad, Gowhar Ali, Wajahat Mahmood, Khwaja Fawad
BACKGROUND: Diabetic neuropathy is the most prevalent, persistent and debilitating complication of diabetes mellitus often coupled with vulvodynia that may present as an isolated symptom or as a part of constellation of other neuropathic abnormalities. OBJECTIVE: Flavonoids have selective affinity for GABA receptors and 6-methoxyflavanone (6-MeOF) is a positive allosteric modulator of GABA responses at human recombinant GABAA receptors. GABAergic and opioidergic system inhibition have been shown to facilitate neuropathic pain...
October 17, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
M Cugno, A Tedeschi, B Frossi, F Bossi, A V Marzano, R Asero
: Background y Objective: Functionally active autoantibodies to IgE and to the high-affinity IgE receptor (FcεRI) can be detected in serum in about 40% of patients with chronic spontaneous urticaria (CSU). Recent studies showed that serum from patients with CSU can induce activation of mast cells, irrespective of whether they carry high-affinity IgE receptors. To evaluate mast cell activation induced by factors in the serum of CSU patients with a molecular weight lower than that of autoantibodies...
October 2016: Journal of Investigational Allergology & Clinical Immunology
Felix M Wensveen, Erik Slinger, Martijn Ha van Attekum, Robert Brink, Eric Eldering
Upon antigen encounter, the responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity. Already before formation of the germinal center, activated B cells of low-affinity are negatively selected in a process that is molecularly not well understood. In this study, we investigated the mechanism behind pre-GC affinity-mediated B cell selection. We applied affinity mutants of HEL antigen and found that rapidly after activation B cells become highly dependent on the cytokine BAFF...
October 20, 2016: Scientific Reports
Navnit Kumar Mishra, Anil Kumar Sharma, Tapan Kumar Mukherjee
Melanoma is a cancer associated with melanocytes of epidermis. There has been a consistent increase in the number of melanoma patients because of the depletion of the ozone layer which makes it of paramount importance to explore the immunogenic potential of various peptides in melanoma therapy. In the current study, a mutated decapeptide (ELAGIGILTV) epitope ID 12941 was taken from the melanoma antigen recognized by T-cells. This epitope displayed relatively better affinity for histocompatibility leukocyte antigen influencing the proliferation of cytotoxic T-cells...
November 2016: Journal of Molecular Modeling
Ana C Puhl, Paul Webb, Igor Polikarpov
Loss-of-function mutation V290M in the ligand-binding domain of the peroxisome proliferator activated receptor γ (PPARγ) is associated with a ligand resistance syndrome (PLRS), characterized by partial lipodystrophy and severe insulin resistance. In this data article we discuss an X-ray diffraction dataset that yielded the structure of PPARγ LBD V290M mutant refined at 2.3 Å resolution, that allowed building of 3D model of the receptor mutant with high confidence and revealed continuous well-defined electron density for the partial agonist diclofenac bound to hydrophobic pocket of the PPARγ...
June 2016: Data in Brief
Andresa H Betti, Camila B Antonio, Thais E T Pompeu, Thaise S Martins, Vivian Herzfeldt, Eveline D Stolz, Carlos A M Fraga, Eliezer Barreiro, François Noël, Stela M K Rates
Aiming to identify new antipsychotic lead-compounds, our group has been working on the design and synthesis of new N-phenylpiperazine derivatives. Here, we characterized LASSBio-1422 as a pharmacological prototype of this chemical series. Adult male Wistar rats and CF1 mice were used for in-vitro and in-vivo assays, respectively. LASSBio-1422 [1 and 5 mg/kg, postoperatively (p.o.)] inhibited apomorphine-induced climbing as well as ketamine-induced hyperlocomotion (1 and 5 mg/kg, p.o.), animal models predictive of efficacy on positive symptoms...
October 13, 2016: Behavioural Pharmacology
Yves Claude Guillaume, Lydie Lethier, Claire André
TRAIL is a member of the TNF family of cytokines which induces apoptosis of cancer cells via its binding to its cognate receptors, DR5 a high affinity site and DR4 a site of low affinity. Our working group has recently demonstrated that nanovectorization of TRAIL with single wall carbon nanotubes (abbreviated NPT) enhanced TRAIL affinity to the high affinity site DR5 and increased pro apoptotic potential in different human tumor cell lines. In this paper, the DR4 low affinity site was immobilized on a chromatographic support and the effect of temperature on a wide temperature range 1°C-50°C was studied to calculate the thermodynamic parameters of the binding of TRAIL and NPT to DR4 and DR5 receptors...
October 12, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Ken G Andersson, Maryam Oroujeni, Javad Garousi, Bogdan Mitran, Stefan Ståhl, Anna Orlova, John Löfblom, Vladimir Tolmachev
The epidermal growth factor receptor (EGFR) is overexpressed in a number of malignant tumors and is a molecular target for several specific anticancer antibodies and tyrosine kinase inhibitors. The overexpression of EGFR is a predictive biomarker for response to several therapy regimens. Radionuclide molecular imaging might enable detection of EGFR overexpression by a non-invasive procedure and could be used repeatedly. Affibody molecules are engineered scaffold proteins, which could be selected to have a high affinity and selectivity to predetermined targets...
October 5, 2016: International Journal of Oncology
Mackenzie L Lauro, Elizabeth A D'Ambrosio, Brian J Bahnson, Catherine Leimkuhler Grimes
Genetic mutations in the innate immune receptor nucleotide-binding oligomerization domain-containing 2 (Nod2) have demonstrated increased susceptibility to Crohn's disease, an inflammatory bowel disease which is hypothesized to be accompanied by changes in the gut microbiota. Nod2 responds to the presence of bacteria, specifically a fragment of the bacterial cell wall, muramyl dipeptide (MDP). The proposed site of this interaction is the leucine-rich repeat (LRR) domain. Surface plasmon resonance and molecular modeling were used to investigate the interaction of the LRR domain with MDP...
October 17, 2016: ACS Infectious Diseases
Jatin Machhi, Navnit Prajapati, Ashutosh Tripathi, Zalak S Parikh, Ashish M Kanhed, Kirti Patel, Prakash P Pillai, Rajani Giridhar, Mange Ram Yadav
Excitotoxicty, a key pathogenic event is characteristic of the onset and development of neurodegeneration. The glutamatergic neurotransmission mediated through different glutamate receptor subtypes plays a pivotal role in the onset of excitotoxicity. The role of NMDA receptor (NMDAR), a glutamate receptor subtype, has been well established in the excitotoxicity pathogenesis. NMDAR overactivation triggers excessive calcium influx resulting in excitotoxic neuronal cell death. In the present study, a series of benzazepine derivatives, with the core structure of 3-methyltetrahydro-3H-benzazepin-2-one, were synthesised in our laboratory and their NMDAR antagonist activity was determined against NMDA-induced excitotoxicity using SH-SY5Y cells...
October 15, 2016: Molecular Neurobiology
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