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Molecular receptor affinity

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https://www.readbyqxmd.com/read/28806065/synthesis-characterization-and-selective-delivery-of-darpin-gold-nanoparticle-conjugates-to-cancer-cells
#1
Sergey Deyev, Galina Proshkina, Anastasiya Ryabova, Francesco Tavanti, Maria Cristina Menziani, Gennady Eidelshtein, Gabriel Avishai, Alexander B Kotlyar
We demonstrate that the designed ankyril repeat protein (DARPin) _9-29, which specifically targets human epidermal growth factor receptor 2 (HER 2), binds tightly to gold nanoparticles (GNPs). Binding of the protein strongly increases the colloidal stability of the particles. The results of experimental analysis and molecular dynamics simulations show that approximately 35 DARPin _9-29 molecules are bound to the surface of a 5 nm GNP and that the binding does not involve the receptor-binding domain of the protein...
August 14, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28805144/a-qm-protein-ligand-investigation-of-anti-psychotic-drugs-with-the-dopamine-d2-receptor-d2r
#2
Ramin Ekhteiari Salmas, Yusuf Serhat Is, Serdar Durdagi, Matthias Stein, Mine Yurtsever
The dopamine D2 Receptor (D2R) is a member of the G-Protein Coupled Receptor (GPCR) family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson's disease. D2R is the target protein of the commonly used anti-psychotic drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone and quetiapine. Due to their significant side effects and nonselective profiles, the discovery of novel drugs has become a challenge for researchers working in this field...
August 14, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28803965/the-great-divide-separation-between-in-vitro-and-in-vivo-effects-of-psncbam-based-cb1-receptor-allosteric-modulators
#3
Thomas F Gamage, Charlotte E Farquhar, Timothy W Lefever, Brian F Thomas, Thuy Nguyen, Yanan Zhang, Jenny L Wiley
While allosteric modulators of the cannabinoid type-1 receptor (CB1) continue to be developed and characterized, the gap between the in vitro and in vivo data is widening, raising questions regarding translatability of their effects and biological relevance. Among the CB1 allosteric modulators, PSNCBAM-1 has received little attention regarding its effects in vivo. Recently, pregnenolone was reported to act as an allosteric modulator of CB1, blocking THC's effects in vitro and in vivo, highlighting the potential of CB1 allosteric modulators for treatment of cannabis intoxication...
August 10, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28799326/glp-1-conjugated-to-rhsa-variants-with-modified-fcrn-binding-properties-impact-on-molecular-structure-and-half-life
#4
Jens Thostrup Bukrinski, Pernille Sønderby, Filipa Antunes, Birgitte Andersen, Esben Gjerloeff Wedebye Schmidt, Guenther H H J Peters, Pernille Harris
Glucagon-like peptide 1 (GLP-1) is a small incretin hormone stimulated by food intake, resulting in an amplification of the insulin response. Though interesting as a drug candidate for the treatment of type 2 diabetes mellitus, its short plasma half-life of less than 3 minutes limits its clinical use. A strategy to extend the half-life of GLP-1 utilizes the long half-life of human serum albumin (HSA) by combining the two via chemical conjugation or genetic fusion. HSA has a plasma half-life of around 21 days owing to its interaction with the neonatal Fc receptor (FcRn) expressed in endothelial cells of blood vessels, which rescues circulating HSA from lysosomal degradation...
August 11, 2017: Biochemistry
https://www.readbyqxmd.com/read/28799176/the-molecular-mechanism-behind-resistance-of-the-kinase-flt3-to-the-inhibitor-quizartinib
#5
Ran Friedman
Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is a drug target for leukaemias. Several potent inhibitors of FLT3 exists, and bind to the inactive form of the enzyme. Unfortunately, resistance due to mutations in the kinase domain of FLT3 limits the therapeutic effects of these inhibitors. As in many other cases, it is not straightforward to explain why certain mutations lead to drug resistance. Extensive fully-atomistic molecular dynamics (MD) simulations of FLT3 were carried out with an inhibited form (FLT-quizartinib complex), a free (apo) form and an active conformation...
August 11, 2017: Proteins
https://www.readbyqxmd.com/read/28797797/synthesis-estrogen-receptor-binding-affinity-and-molecular-docking-of-pyrimidine-piperazine-chromene-and-quinoline-conjugates
#6
Iram Parveen, Naseem Ahmed, Danish Idrees, Parvez Khan, Md Imtaiyaz Hassan
Substituted 2-amino-7-((6-(4-(2-hydroxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-yl)oxy)-4-phenyl-4H-chromene-3-carbonitriles and 2-amino-7-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)oxy)-4-phenyl-1,4-dihydroquinoline-3-carbonitriles were synthesized via an efficient multi-component one pot synthesis under mild conditions. These compounds 1-20 were evaluated against human breast cancer cell lines (MCF-7) and human embryonic kidney cells (HEK293) for cytotoxic activities. Among them, compounds 6, 7, 15, 17 and 19 showed better anti-proliferative activities as (IC50 value 48±1...
July 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28796245/dioscin-induces-prostate-cancer-cell-apoptosis-through-activation-of-estrogen-receptor-%C3%AE
#7
Xufeng Tao, Lina Xu, Lianhong Yin, Xu Han, Yan Qi, Youwei Xu, Shasha Song, Yanyan Zhao, Jinyong Peng
Recent researches have shown that estrogen receptor-β (ERβ) activator may be a potent anticancer agent for prostate cancer (PCa), and our previous study also indicated that dioscin can upregulate the expression of ERβ in MC3T3-E1 cell. In the present work, the activity and mechanism of dioscin, a natural product, against PCa were investigated. The results showed that dioscin markedly inhibited cell viability, colony formation, motility and induced apoptosis in PC3 cells. Moreover, dioscin disrupted the formation of PC3 cell-derived mammospheres and reduced aldehyde dehydrogenase (ALDH) level and the CD133(+)/CD44(+) cells, indicating that dioscin had a potent inhibitory activity on prostate cancer stem cells (PCSCs)...
August 10, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28795601/poly-glutamic-dendrimer-based-conjugates-for-cancer-vaccination-a-computational-design-for-targeted-delivery-of-antigens
#8
L I F Moura, N Martinho, L C Silva, T S Barata, S Brocchini, H F Florindo, M Zloh
Computational techniques are useful to predict interaction models and molecular properties for the design of drug delivery systems, such as dendrimers. This work evaluated the impact of surface modifications of mannosamine-conjugated multifunctional poly(glutamic acid) (PG)-dendrimers as nanocarriers of the tumour associated antigens (TAA) MART-1, gp100:44 and gp100:209. Molecular dynamics simulations and docking studies were performed. Nitrobenzoxadiazole (NBD)-PG-G4-dendrimer displayed 64 carboxylic groups, however, the Frontier Molecular Orbital Theory study evidenced that only 32 of those were available to form covalent bonds...
August 10, 2017: Journal of Drug Targeting
https://www.readbyqxmd.com/read/28792759/effect-of-nitrogen-atom-substitution-in-a3-adenosine-receptor-binding-n-4-6-diarylpyridin-2-yl-acetamides-as-potent-and-selective-antagonists
#9
Jhonny Azuaje, Willem Jespers, Vicente Yaziji, Ana Mallo, María Majellaro, Olga Caamaño, María I Loza, María I Cadavid, José M Brea, Johan Åqvist, Eddy Sotelo, Hugo Gutiérrez de Terán
We report the first family of 2-acetamidopyridines as potent and selective A3 adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit antagonistic effect with excellent affinity (Ki < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, by molecular dynamics and free energy perturbation simulations we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site...
August 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28777495/increased-conformational-flexibility-of-a-macrocycle-receptor-complex-contributes-to-reduced-dissociation-rates
#10
Adrian Glas, Eike-Christian Wamhoff, Dennis M Krüger, Christoph Rademacher, Tom N Grossmann
Constraining a peptide in its bioactive conformation via macrocyclization represents a powerful strategy to design modulators of challenging biomolecular targets. This holds particularly true for the development of inhibitors of protein-protein interactions which often involve interfaces lacking defined binding pockets. Such flat surfaces are demanding targets for traditional small molecules rendering macrocyclic peptides promising scaffolds for novel therapeutics. However, the contribution of peptide dynamics to binding kinetics is barely understood which impedes the design process...
August 4, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28774842/bioinspired-butyrate-functionalized-nanovehicles-for-targeted-oral-delivery-of-biomacromolecular-drugs
#11
Lei Wu, Min Liu, Wei Shan, Xi Zhu, Lijia Li, Zhirong Zhang, Yuan Huang
Ligand-functionalization can increase the affinity of nanoparticles (NPs) with targeted cells. However, one major defect of ligands still exists in oral administration: limited receptor recognition. The hindrance of mucus network and deactivation of enzymes severely challenge the targeting efficiency of macromolecular ligands. Inspired by "molecular exchange" between intestinal microbiota and host cells, we anchored microbiota metabolite butyrate on classical "mucus-inert" polyethylene glycol (PEG) NPs. Butyrate has unique advantages of low molecule weight, high hydrophilicity and chemical stability...
August 1, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28771010/systems-pharmacology-dissection-of-multi-scale-mechanisms-of-action-for-herbal-medicines-in-treating-rheumatoid-arthritis
#12
Jinghui Wang, Yan Li, Yinfeng Yang, Jian Du, Miaoqing Zhao, Feng Lin, Shuwei Zhang, Bin Wang
As a chronic inflammatory and angiogenic disease with increased morbidity and mortality, rheumatoid arthritis (RA) is characterized by the proliferation of synovial tissue and the accumulation of excessive mononuclear infiltration, which always results in the joint deformity, disability, and eventually the destruction of the bone and cartilage. Traditional Chinese Medicine (TCM), with rich history of proper effectiveness in treating the inflammatory joint disease containing RA, has long combated such illness from, actually, an integrative and holistic point of view...
August 3, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28767081/new-insights-in-the-design-of-bioactive-peptides-and-chelating-agents-for-imaging-and-therapy-in-oncology
#13
REVIEW
Anna Lucia Tornesello, Luigi Buonaguro, Maria Lina Tornesello, Franco Maria Buonaguro
Many synthetic peptides have been developed for diagnosis and therapy of human cancers based on their ability to target specific receptors on cancer cell surface or to penetrate the cell membrane. Chemical modifications of amino acid chains have significantly improved the biological activity, the stability and efficacy of peptide analogues currently employed as anticancer drugs or as molecular imaging tracers. The stability of somatostatin, integrins and bombesin analogues in the human body have been significantly increased by cyclization and/or insertion of non-natural amino acids in the peptide sequences...
August 2, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28766941/a-computational-investigation-of-small-molecule-engagement-of-hot-spots-at-protein-protein-interaction-interfaces
#14
David Xu, Yubing Si, Samy O Meroueh
The binding affinity of a protein-protein interaction is concentrated at amino acids known as hot spots. It has been suggested that small molecules disrupt protein-protein interactions by either (i) engaging receptor protein hot spots; or (ii) mimicking hot spots of the protein ligand. Yet, to date, no systematic studies have been done to explore how effectively existing small-molecule protein-protein interaction inhibitors mimic or engage hot spots at protein interfaces. Here, we employ explicit-solvent molecular dynamics simulations and end-point MM-GBSA free energy calculations to explore this question...
August 2, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28766155/a-facile-synthesis-of-amide-based-receptors-under-microwave-conditions-investigation-of-their-anion-recognition-properties-by-experimental-and-computational-tools
#15
Gülşen Öztürk, Salih Subari, Sevil Şeker, Mahmut Toğrul, Şafak Özhan Kocakay, Selami Ercan, Necmettin Pirinççioğlu
Two novel amide-based receptors were synthesized under microwave irradiation. Their chemical structures were confirmed by IR, (1)H NMR, (13)C NMR, and elemental analysis. The binding properties of these amide-based receptors to various anions (H2PO4(-), HSO4(-), C6H5CO2(-), CH3CO2(-), ClO4(-), F(-), Cl(-), and Br(-)) were examined by UV titration in THF at 20 °C. The results indicated that the receptors form 1:1 complexes with anions and they have the strongest affinity for fluoride (F(-)) among the anions considered...
September 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28765074/estrogenic-effects-associated-with-bisphenol-a-exposure-in-male-zebrafish-danio-rerio-is-associated-with-changes-of-endogenous-17%C3%AE-estradiol-and-gene-specific-dna-methylation-levels
#16
Fei Zhao, Penghao Wei, Jun Wang, Miao Yu, Xiaona Zhang, Hua Tian, Wei Wang, Shaoguo Ru
The binding affinity of bisphenol A (BPA) to estrogen receptors (ERs) is much lower than that of 17β-estradiol (E2), and whether there are other molecular mechanisms responsible for the estrogenic action of BPA in vivo currently remains unknown. The objective of this study was to explore the potential association between the estrogenic effect induced by bisphenol A in vivo and changes of endogenous E2 and gene specific DNA methylation levels. After a waterborne exposure of male zebrafish to 500, 1000, or 1500μg/L of BPA for 21d, vitellogenin (VTG) concentration in whole body homogenate, plasma E2 and testosterone levels, hepatic ERs mRNA expressions, gonadal cyp19a1a and cyp17a1 mRNA expressions, and methylation levels of hepatic esr1 and gonadal cyp19a1a's promoters were determined...
July 29, 2017: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28761153/pla2r-binds-to-the-annexin-a2-s100a10-complex-in-human-podocytes
#17
Maryline Fresquet, Thomas A Jowitt, Edward A McKenzie, Matthew D Ball, Michael J Randles, Rachel Lennon, Paul E Brenchley
Phospholipase A2 receptor (PLA2R) is a member of the mannose receptor family found in podocytes in human kidney. PLA2R is the target of the autoimmune disease, membranous nephropathy, characterised by production of anti-PLA2R autoantibodies which bind to the podocyte. However the function of PLA2R in health and in disease remains unclear. To gain insight into the molecular mechanisms of PLA2R function, we searched for its endogenous binding partners. Proteomic analysis identified annexinA2 as a potential interactor with the extracellular domains of PLA2R...
July 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28760338/structural-dynamics-of-gi%C3%AE-protein-revealed-by-single-molecule-fret
#18
Yongping Zhu, Lei Zhang, Xuejun C Zhang, Yongfang Zhao
The heterotrimeric G proteins (Gαβγ) act as molecular switches to mediate signal transduction from G protein-coupled receptors to downstream effectors. Upon interaction with an activated receptor, G protein exchanges its bound GDP with GTP, stimulating downstream signal transmission. Release of GDP requires a structural rearrangement between the GTPase domain and helical domain of the Gα subunit. Here, we used single molecule fluorescence resonance energy transfer (smFRET) technique to study the conformational dynamics of these two domains in the apo state and in the binding of different ligands...
July 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28759825/binding-free-energy-calculations-using-mmpb-gbsa-approaches-for-pamam-g4-drug-complexes-at-neutral-basic-and-acid-ph-conditions
#19
Alberto Martínez-Muñoz, Martiniano Bello, Aurelio Romero-Castro, Rolando Alberto Rodríguez-Fonseca, João Rodrigues, Víctor Armando Sánchez-Espinosa, José Correa-Basurto
Dendrimers are synthetic macromolecules with a highly-branched structure and high concentration of surface groups. Among dendrimers, Poly(amidoamine) (PAMAM) has received substantial attention as a novel drug carrier and delivery system. Depending on the generation and type of terminal groups, dendrimer toxicity could change and include cytotoxicity. Although PAMAM is water soluble, molecular modeling of the dendrimer-drug complex is considered challenging for exploring the conformational mobility of dendrimers and atomic specific interactions during the dendrimer-drug association...
July 19, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28757062/design-synthesis-and-biological-evaluation-of-novel-3-oxo-4-oxa-5%C3%AE-androst-17%C3%AE-amide-derivatives-as-dual-5%C3%AE-reductase-inhibitors-and-androgen-receptor-antagonists
#20
Kejing Lao, Jie Sun, Chong Wang, Ying Wang, Qidong You, Hong Xiao, Hua Xiang
Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities...
May 27, 2017: Bioorganic & Medicinal Chemistry Letters
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