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Molecular receptor affinity

Thomas F Gamage, Charlotte E Farquhar, Timothy W Lefever, Julie A Marusich, Richard C Kevin, Iain S McGregor, Jenny L Wiley, Brian F Thomas
Synthetic cannabinoids are a class of novel psychoactive substances that exhibit high affinity at the cannabinoid type-1 (CB1) receptor and produce effects similar to those of THC, the primary psychoactive constituent of cannabis. Illicit drug manufacturers are continually circumventing laws banning the sale of synthetic cannabinoids by synthesizing novel structures and doing so with little regard for their potential impact on pharmacological and toxicological effects. Synthetic cannabinoids produce a wide range of effects including cardiotoxicity, seizure activity, and kidney damage and can result in death...
March 16, 2018: Journal of Pharmacology and Experimental Therapeutics
Ekaterina M Savelieva, Vladimir E Oslovsky, Dmitry S Karlov, Nikolay N Kurochkin, Irina A Getman, Sergey N Lomin, Georgy V Sidorov, Sergey N Mikhailov, Dmitry I Osolodkin, Georgy A Romanov
Biological effects of hormones in both plants and animals are based on high-affinity interaction with cognate receptors resulting in their activation. The signal of cytokinins, classical plant hormones, is perceived in Arabidopsis by three homologous membrane receptors: AHK2, AHK3, and CRE1/AHK4. To study the cytokinin-receptor interaction, we used 25 derivatives of potent cytokinin N6 -benzyladenine (BA) with substituents in the purine heterocycle and/or in the side chain. The study was focused primarily on individual cytokinin receptors from Arabidopsis...
March 12, 2018: Phytochemistry
Hong Truong, Leonard G Gomella, Mathew L Thakur, Edouard J Trabulsi
PURPOSE: Current approaches to prostate cancer screening and diagnosis are plagued with limitations in diagnostic accuracy. There is a compelling need for biomolecular imaging that will not only detect prostate cancer early but also distinguish prostate cancer from benign lesions accurately. In this topic paper, we review evidence that supports further investigation of VPAC1-targeted PET/CT imaging in the primary diagnosis of prostate cancer. METHODS: A non-systematic review of Medline/PubMed was performed...
March 14, 2018: World Journal of Urology
Megan Sjodt, Ramsay Macdonald, Joanna D Marshall, Joseph Clayton, John S Olson, Martin L Phillips, David A Gell, Jeff Wereszczynski, Robert T Clubb
Staphylococcus aureus is a leading cause of life-threatening infections in the United States. It actively acquires the essential nutrient iron from human hemoglobin (Hb) using the iron-regulated surface-determinant (Isd) system. This process is initiated when the closely related bacterial IsdB and IsdH receptors bind to Hb and extract its hemin through a conserved tri-domain unit that contains two NEAr iron Transporter (NEAT) domains that are connected by a helical linker domain. Previously, we demonstrated that the tri-domain unit within IsdH (IsdHN2N3 ) triggers hemin release by distorting Hb's F-helix...
March 14, 2018: Journal of Biological Chemistry
Rebecca C Allsopp, Sudad Dayl, Anfal Bin Dayel, Ralf Schmid, Richard J Evans
P2X7 receptor (P2X7Rs) activation requires ~ 100 fold higher concentrations of ATP than other P2XR subtypes. Such high levels are found during cellular stress and P2X7Rs consequently contribute to a range of pathophysiological conditions. We have used chimeric and mutant P2X7Rs, coupled with molecular modelling, to produce a validated model of the binding mode of the subtype selective antagonist A438079 at an inter-subunit allosteric site. Within the allosteric site large effects on antagonist action were found for point mutants of residues, F88A, D92A, F95A and F103A that were conserved or similar between sensitive/insensitive P2XR subtypes suggesting that these side chain interactions were not solely responsible for high affinity antagonist binding...
March 13, 2018: Molecular Pharmacology
Francesco Spinelli, Ahmed Haider, Annamaria Toscano, Maria Laura Pati, Claudia Keller, Francesco Berardi, Nicola Antonio Colabufo, Carmen Abate, Simon M Ametamey
The Sigma-1 receptor (Sig-1R) has been described as a pluripotent modulator of distinct physiological functions and its involvement in various central and peripheral pathological disorders has been demonstrated. However, further investigations are required to understand the complex role of the Sig-1R as a molecular chaperon. A specific PET radioligand would provide a powerful tool in Sig-1R related studies. As part of our efforts to develop a Sig-1R PET radioligand that shows antagonistic properties, we investigated the suitability of 1-(4-(6-methoxynaphthalen-1-yl)butyl)-4-methylpiperidine (designated PB212) for imaging Sig-1R...
2018: American Journal of Nuclear Medicine and Molecular Imaging
Célia Gautier, Sophie-Penelope Guenin, Isabelle Riest-Fery, Tahlia Jade Perry, Céline Legros, Olivier Nosjean, Valerie Simonneaux, Frank Grützner, Jean A Boutin
Melatonin is a neurohormone produced in both animals and plants. It binds at least three G-protein-coupled receptors: MT1 and MT2, and Mel1cGPR. Mammalian GPR50 evolved from the reptilian/avian Mel1c and lost its capacity to bind melatonin in all the therian mammal species that have been tested. In order to determine if binding is lost in the oldest surviving mammalian lineage of monotremes we investigated whether the melatonin receptor has the ability to bind melatonin in the platypus (Ornithorhynchus anatinus), and evaluated its pharmacological profile...
2018: PloS One
Mary K Phillips-Jones, Stephen E Harding
In this review, we discuss mechanisms of resistance identified in bacterial agents Staphylococcus aureus and the enterococci towards two priority classes of antibiotics-the fluoroquinolones and the glycopeptides. Members of both classes interact with a number of components in the cells of these bacteria, so the cellular targets are also considered. Fluoroquinolone resistance mechanisms include efflux pumps (MepA, NorA, NorB, NorC, MdeA, LmrS or SdrM in S. aureus and EfmA or EfrAB in the enterococci) for removal of fluoroquinolone from the intracellular environment of bacterial cells and/or protection of the gyrase and topoisomerase IV target sites in Enterococcus faecalis by Qnr-like proteins...
March 10, 2018: Biophysical Reviews
Hugo Aguilar-Díaz, Karen E Nava-Castro, Galileo Escobedo, Lenin Domínguez-Ramírez, Martín García-Varela, Víctor H Del Río-Araiza, Margarita I Palacios-Arreola, Jorge Morales-Montor
BACKGROUND: We have previously reported that progesterone (P4 ) has a direct in vitro effect on the scolex evagination and growth of Taenia solium cysticerci. Here, we explored the hypothesis that the P4 direct effect on T. solium might be mediated by a novel steroid-binding parasite protein. METHODS: By way of using immunofluorescent confocal microscopy, flow cytometry analysis, double-dimension electrophoresis analysis, and sequencing the corresponding protein spot, we detected a novel PGRMC in T...
March 9, 2018: Parasites & Vectors
Zhibin Liang, Qing X Li
The π-cation interaction that differs from the cation-π interaction is a valuable concept in molecular design of pharmaceuticals and pesticides. In this Perspective we present an up-to-date review (from 1995 to 2017) on bioactive molecules involving π-cation interactions with the recognition site, and categorize into systems of inhibitor-enzyme, ligand-receptor, ligand-transporter, and hapten-antibody. The concept of π-cation interactions offers use of π systems in a small molecule to enhance the binding affinity, specificity, selectivity, lipophilicity, bioavailability, and metabolic stability, which are physiochemical features desired for drugs and pesticides...
March 9, 2018: Journal of Agricultural and Food Chemistry
Kerry R Belton, Yuan Tian, Limin Zhang, Mallappa Anitha, Philip B Smith, Gary H Perdew, Andrew D Patterson
The liver and the mammary gland have complementary metabolic roles during lactation. Substrates (e.g., glucose and amino acids) synthesized by the liver are released into the circulation and are taken up by the mammary gland for milk production (e.g., lactose and the glycerol backbone of milk triglycerides). The aryl hydrocarbon receptor (AHR) has been identified as a lactation regulator in mice, and its activation has been associated with myriad morphological, molecular, and functional defects such as stunted gland development, decreased milk production, and changes in gene expression...
March 9, 2018: Journal of Proteome Research
Mohammed Benadallah, Oualid Talhi, Fatiha Nouali, Nourredine Choukchou-Braham, Khaldoun Bachari, Artur M S Silva
The present review deals with the progress in medicinal chemistry of spirocyclic compounds, a wider class of natural and synthetic organic molecules, defined as a hybrid of two molecular entities covalently linked via a unique tetrahedral carbon. This spiro central carbon confers to the molecules a tridimensional structurally oriented framework, which is found in many medicinally relevant compounds, a well-known example is the anti-hypertensive spironolactone. Various bioactive natural products possess the privileged spiro linkage and different chemo-types thereof become synthetically accessible since the 20th century...
March 9, 2018: Current Medicinal Chemistry
Yuejie Zhao, Jeong Yeh Yang, David F Thieker, Yongmei Xu, Chengli Zong, Geert-Jan Boons, Jian Liu, Robert J Woods, Kelley W Moremen, I Jonathan Amster
Roundabout 1 (Robo1) interacts with its receptor Slit to regulate axon guidance, axon branching, and dendritic development in the nervous system and to regulate morphogenesis and many cell functions in the nonneuronal tissues. This interaction is known to be critically regulated by heparan sulfate (HS). Previous studies suggest that HS is required to promote the binding of Robo1 to Slit to form the minimal signaling complex, but the molecular details and the structural requirements of HS for this interaction are still unclear...
March 8, 2018: Journal of the American Society for Mass Spectrometry
I N Goronzy, R J Rawle, S G Boxer, P M Kasson
Influenza virus infects cells by binding to sialylated glycans on the cell surface. While the chemical structure of these glycans determines hemagglutinin-glycan binding affinity, bimolecular affinities are weak, so binding is avidity-dominated and driven by multivalent interactions. Here, we show that membrane spatial organization can control viral binding. Using single-virus fluorescence microscopy, we demonstrate that the sterol composition of the target membrane enhances viral binding avidity in a dose-dependent manner...
February 28, 2018: Chemical Science
Meixi Hao, Siyuan Hou, Lingjing Xue, Haoliang Yuan, Lulu Zhu, Cong Wang, Bin Wang, Chunming Tang, Can Zhang
Vitamin D3 receptor (VDR), belonging to the nuclear receptor superfamily, is a potential molecular target for anticancer drug discovery. In this study, a series of non-steroidal vitamin D analogs with phenyl-pyrrolyl pentane skeleton were synthesized with therapeutic potential for cancer treatment. Among them, 11b and 11g were identified as the most effective agents in reducing the viability of four cancer cell lines, particularly breast cancer cells, with IC50 values in the submicromolar concentration range...
March 8, 2018: Journal of Medicinal Chemistry
Xiaozheng Zhang, Fengchao Cui, Hongqian Chen, Tianshu Zhang, Kecheng Yang, Yibo Wang, Zhenyan Jiang, Kenner C Rice, Linda R Watkins, Mark R Hutchinson, Yunqi Li, Yinghua Peng, Xiaohui Wang
The opioid inactive isomer (+)-naltrexone is one of the rare Toll-like receptor 4 (TLR4) antagonists with good blood-brain barrier (BBB) permeability, which is a lead with promising potential for treating neuropathic pain and drug addiction. (+)-Naltrexone targets the lipopolysaccharides (LPS) binding pocket of myeloid differentiation protein 2 (MD-2) and blocks innate immune TLR4 signaling. However, the details of the molecular interactions of (+)-naltrexone and its derivatives with MD-2 are not fully understood, which hinders the ligand-based drug discovery...
March 8, 2018: Journal of Chemical Information and Modeling
Yan Xia, Xiliang Zheng, Erkang Wang, Dongfeng Li, Ruibin Hou, Jin Wang
Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1 , A2A , A2B and A3 , which belong to the G-protein-coupled receptor superfamily. The human A3 AR (hA3 AR) subtype is implicated in several cytoprotective functions. Therefore, hA3 AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anti-cancer and cardioprotective agents. Here, we prepared novel adenosine derivatives with indole moiety as hA3 AR ligands...
February 2018: Royal Society Open Science
Paula G Slater, Sebastian E Gutierrez-Maldonado, Katia Gysling, Carlos F Lagos
The corticotropin-releasing factor (CRF) system is a key mediator of the stress response and addictive behavior. The CRF system includes four peptides: The CRF system includes four peptides: CRF, urocortins I-III, CRF binding protein (CRF-BP) that binds CRF with high affinity, and two class B G-protein coupled receptors CRF1 R and CRF2 R. CRF-BP is a secreted protein without significant sequence homology to CRF receptors or to any other known class of protein. Recently, it has been described a potentiation role of CRF-BP over CRF signaling through CRF2 R in addictive-related neuronal plasticity and behavior...
2018: Frontiers in Endocrinology
Valentina Indio, Annalisa Astolfi, Giuseppe Tarantino, Milena Urbini, Janice Patterson, Margherita Nannini, Maristella Saponara, Lidia Gatto, Donatella Santini, Italo F do Valle, Gastone Castellani, Daniel Remondini, Michelangelo Fiorentino, Margaret von Mehren, Giovanni Brandi, Guido Biasco, Michael C Heinrich, Maria Aabbondanza Pantaleo
Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha ( PDGFRA ) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein-ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course...
March 4, 2018: International Journal of Molecular Sciences
Sangeeta Ray Banerjee, Xiaolei Song, Xing Yang, Il Minn, Ala Lisok, Yanrong Chen, Martin G Pomper, Peter C M van Zijl, Michael McMahon, Jian Chen
Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is an innovative molecular imaging technique in which contrast agents are labeled by saturating their exchangeable protons spins by radio frequency irradiation. Salicylic acid and its analogues are a promising class of highly sensitive, diamagnetic CEST agents. We synthesized polymeric agents grafted with salicylic acid moieties and a known high-affinity ligand targeting prostate-specific membrane antigen (PSMA) in a ~10:1 molar ratio to provide sufficient MRI sensitivity and receptor specificity...
March 5, 2018: Chemistry: a European Journal
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