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https://www.readbyqxmd.com/read/28103537/hybrids-of-thienopyrimidinones-and-thiouracils-as-anti-tubercular-agents-sar-and-docking-studies
#1
Mahesh M Pisal, Laxman U Nawale, Manoj D Patil, Sujit G Bhansali, Jayant M Gajbhiye, Dhiman Sarkar, Subhash P Chavan, Hanumant B Borate
A number of hybrid molecules containing thienopyrimidinones and thiouracil moieties were designed, synthesized and tested against Mycobacterium tuberculosis H37Ra wherein it was observed that the compounds 11-14 exhibited antitubercular activity in vitro (MIC 7.6-19.1 μg/mL, 12-35 μM) against dormant stage while the compound 15 exhibited antitubercular activity in vitro against dormant (MIC 23.4 μg/mL, 41 μM) as well as active (MIC 25.4 μg/mL, 45 μM) stage. Structural modifications of the compound 15 were carried out to study the structure-activity relationship and it was observed that the compound 18 exhibited antitubercular activity comparable to the compound 15...
January 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28103441/enantio-specific-allosteric-modulation-of-cannabinoid-1-receptor
#2
Robert B Laprairie, Pushkar M Kulkarni, Jeffrey R Deschamps, Melanie E M Kelly, David R Janero, Maria G Cascio, Lesley A Stevenson, Roger G Pertwee, Terry Kenakin, Eileen M Denovan-Wright, Ganesh A Thakur
The cannabinoid 1 receptor (CB1R) is one of the most widely expressed metabotropic G protein-coupled receptors in brain, and its participation in various (patho)physiological processes has made CB1R activation a viable therapeutic modality. Adverse psychotropic effects limit the clinical utility of CB1R orthosteric agonists and have promoted the search for CB1R positive allosteric modulators (PAMs) with the promise of improved drug-like pharmacology and enhanced safety over typical CB1R agonists. In this study, we describe the synthesis and in vitro and ex vivo pharmacology of the novel allosteric CB1R modulator GAT211 (racemic) and its resolved enantiomers, GAT228 (R) and GAT229 (S)...
January 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28103242/genome-wide-binding-of-posterior-hoxa-d-transcription-factors-reveals-subgrouping-and-association-with-ctcf
#3
Ivana Jerković, Daniel M Ibrahim, Guillaume Andrey, Stefan Haas, Peter Hansen, Catrin Janetzki, Irene González Navarrete, Peter N Robinson, Jochen Hecht, Stefan Mundlos
Homeotic genes code for key transcription factors (HOX-TFs) that pattern the animal body plan. During embryonic development, Hox genes are expressed in overlapping patterns and function in a partially redundant manner. In vitro biochemical screens probing the HOX-TF sequence specificity revealed largely overlapping sequence preferences, indicating that co-factors might modulate the biological function of HOX-TFs. However, due to their overlapping expression pattern, high protein homology, and insufficiently specific antibodies, little is known about their genome-wide binding preferences...
January 19, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28103240/rfx2-stabilizes-foxj1-binding-at-chromatin-loops-to-enable-multiciliated-cell-gene-expression
#4
Ian K Quigley, Chris Kintner
Cooperative transcription factor binding at cis-regulatory sites in the genome drives robust eukaryotic gene expression, and many such sites must be coordinated to produce coherent transcriptional programs. The transcriptional program leading to motile cilia formation requires members of the DNA-binding forkhead (Fox) and Rfx transcription factor families and these factors co-localize to cilia gene promoters, but it is not clear how many cilia genes are regulated by these two factors, whether these factors act directly or indirectly, or how these factors act with specificity in the context of a 3-dimensional genome...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28103138/discovery-of-a-novel-splice-variant-of-fcar-cd89-unravels-sequence-segments-necessary-for-efficient-secretion-a-story-of-bad-signal-peptides-and-good-ones-that-nevertheless-do-not-make-it
#5
Wai-Heng Lua, Wei-Li Ling, Chinh Tran-To Su, Joshua Yi Yeo, Chandra Shekhar Verma, Birgit Eisenhaber, Frank Eisenhaber, Samuel Ken-En Gan
The IgA receptor, Fcar (CD89) consists of five sequence segments: two segments (S1, S2) forming the potential signal peptide, two extracellular EC domains that include the IgA binding site, and the transmembrane and cytoplasmic tail (TM/C) region. Numerous Fcar splice variants have been reported with various combinations of the sequence segments mentioned above. Here, we report a novel splice variant termed variant APD isolated from a healthy volunteer that lacks only the IgA-binding EC1 domain. Despite possessing the complete signal peptide S1+S2, the variant APD is only found in the intracellular space whereas the wild-type variant 1 is efficiently secreted and variant 4 leaks to the extracellular space...
January 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28103015/antimicrobial-activity-ame-resistance-and-translation-inhibition-studies-of-anthraquinone-neomycin-conjugates
#6
Natalya N Degtyareva, Changjun Gong, Sandra Story, Nathanael Levinson, Adegboyega K Oyelere, Keith D Green, Sylvie Garneau-Tsodikova, Dev Priya Arya
The antibacterial effects of aminoglycosides are based on their association with the A-site of bacterial ribosomal RNA and interference with the translational process in the bacterial cell, causing cell death. The clinical use of aminoglycosides is complicated by resistance and side effects, some of which arise from their interactions with the human mitochondrial 12S rRNA and its deafness-associated mutations, C1494U and A1555G. We report a rapid assay that allows screening of aminoglycoside compounds to these classes of rRNAs...
January 19, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28102866/the-dna-target-determines-the-dimerization-partner-selected-by-bhlhz-like-hybrid-proteins-ahrjun-and-arntfos
#7
Ichiro Inamoto, Gang Chen, Jumi A Shin
The molecular basis of protein-partner selection and DNA binding of the basic helix-loop-helix (bHLH) and basic region-leucine zipper (bZIP) superfamilies of dimeric transcription factors is fundamental toward understanding gene regulation. Because these families share structural similarities, we swapped the bHLH and leucine zipper (LZ) modules between families to uncover how individual modules influence protein-partnering and protein:DNA complexation. We previously described ArntFos, a bHLHZ-like hybrid of the bHLH domain from the bHLH/PAS protein Arnt and LZ from the bZIP protein c-Fos, binding to the Arnt E-box site (TCACGTGA) as a homodimer...
January 19, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28102733/plk1-polo-like-kinase-1-inhibits-mtor-complex-1-and-promotes-autophagy
#8
Stefanie Ruf, Alexander Martin Heberle, Miriam Langelaar-Makkinje, Sara Gelino, Deepti Wilkinson, Carolin Gerbeth, Jennifer Jasmin Schwarz, Birgit Holzwarth, Bettina Warscheid, Chris Meisinger, Marcel A T M van Vugt, Ralf Baumeister, Malene Hansen, Kathrin Thedieck
Mechanistic target of rapamycin complex 1 (MTORC1) and PLK1 (polo like kinase 1) are major drivers of cancer cell growth and proliferation, and inhibitors of both protein kinases are currently being investigated in clinical studies. To date, MTORC1's and PLK1's functions are mostly studied separately, and reports on their mutual crosstalk are scarce. Here, we identify PLK1 as a physical MTORC1 interactor in human cancer cells. PLK1 inhibition enhances MTORC1 activity under nutrient sufficiency and in starved cells, and PLK1 directly phosphorylates the MTORC1 component RPTOR/RAPTOR in vitro...
January 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28102375/the-dynamic-binding-of-cholesterol-to-the-multiple-sites-of-c99-as-revealed-by-coarse-grained-and-all-atom-simulations
#9
Cheng-Dong Li, Qin Xu, Ruo-Xu Gu, Jing Qu, Dong-Qing Wei
It is generally believed that the etiology of Alzheimer's disease (AD) is closely related to the amyloid-β polypeptides, produced from γ-secretase cleavage of C99. There is preliminary evidence that cholesterol directly activates γ-secretase cleavage of C99 through mechanisms that have not been understood so far. In this article, coarse-grained (CG) and all-atom (AT) simulations were employed to investigate the association between C99 and cholesterol, which is essential for our understanding of the role of cholesterol in the amyloidogenic pathway...
January 19, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28102315/methyl-cytosine-driven-structural-changes-enhance-adduction-kinetics-of-an-exon-7-fragment-of-the-p53-gene
#10
Spundana Malla, Karteek Kadimisetty, You-Jun Fu, Dharamainder Choudhary, John B Schenkman, James F Rusling
Methylation of cytosine (C) at C-phosphate-guanine (CpG) sites enhances reactivity of DNA towards electrophiles. Mutations at CpG sites on the p53 tumor suppressor gene that can result from these adductions are in turn correlated with specific cancers. Here we describe the first restriction-enzyme-assisted LC-MS/MS sequencing study of the influence of methyl cytosines (MeC) on kinetics of p53 gene adduction by model metabolite benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), using methodology applicable to correlate gene damage sites for drug and pollutant metabolites with mutation sites...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28102201/direct-pip2-binding-mediates-stable-oligomer-formation-of-the-serotonin-transporter
#11
Andreas Anderluh, Tina Hofmaier, Enrico Klotzsch, Oliver Kudlacek, Thomas Stockner, Harald H Sitte, Gerhard J Schütz
The human serotonin transporter (hSERT) mediates uptake of serotonin from the synaptic cleft and thereby terminates serotonergic signalling. We have previously found by single-molecule microscopy that SERT forms stable higher-order oligomers of differing stoichiometry at the plasma membrane of living cells. Here, we report that SERT oligomer assembly at the endoplasmic reticulum (ER) membrane follows a dynamic equilibration process, characterized by rapid exchange of subunits between different oligomers, and by a concentration dependence of the degree of oligomerization...
January 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28102076/kinobead-and-single-shot-lc-ms-profiling-identifies-selective-pkd-inhibitors
#12
Martin Golkowski, Rama Subba Rao Vidadala, Chloe K Lombard, Hyong Won Suh, Dustin J Maly, Shao-En Ong
ATP-competitive protein kinase inhibitors are important research tools and therapeutic agents. Because there are >500 human kinases that contain highly conserved active sites, the development of selective inhibitors is extremely challenging. Methods to rapidly and efficiently profile kinase inhibitor targets in cell lysates are urgently needed to discover selective compounds and to elucidate the mechanisms of action for polypharmacological inhibitors. Here, we describe a protocol for microgram-scale chemoproteomic profiling of ATP-competitive kinase inhibitors using kinobeads...
January 19, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28101682/synthesis-spectral-and-extended-spectrum-beta-lactamase-studies-of-transition-metal-tetraaza-macrocyclic-complexes
#13
Dinesh Kumar, Nutan Sharma, Manjula Nair
Urinary tract infections commonly occur in humans due to microbial pathogens invading the urinary tract, which can bring about a range of clinical symptoms and potentially fatal sequelae. The present study is aimed at addressing the development of a new antimicrobial agent against extended spectrum beta lactamase (ESBL) producing E. coli bacteria. We have synthesised some biologically potent (NNNN) donor macrocycles (L 1  = dibenzo[f,n]dipyrido[3,4-b:4',3'-j][1,4,9,12]tetraazacyclohexadecine-6,11,18,23(5H,12H, 7H, 24H)-tetraone, and L 2  = 6,12,19,25-tetraoxo-4,6,11,12,16,18,23,24-octahydrotetrabenzo [b,g,k,p][1,5,10,14]tetra azacyclooctadecine-2,13-dicarboxylic acid) and their Ti and Zr metal complexes in alcoholic media using microwave protocol...
January 18, 2017: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/28101571/upregulation-of-mir-146a-by-yy1-depletion-correlates-with-delayed-progression-of-prostate-cancer
#14
Yeqing Huang, Tao Tao, Chunhui Liu, Han Guan, Guangyuan Zhang, Zhixin Ling, Lei Zhang, Kai Lu, Shuqiu Chen, Bin Xu, Ming Chen
Previously published studies explained that the excessive expression of miR-146a influences the prostate cancer (PCa) cells in terms of apoptosis, progression, and viability. Although miR-146a acts as a tumor suppressor, current knowledge on the molecular mechanisms that controls its expression in PCa is limited. In this study, gene set enrichment analysis (GSEA) showed negatively enriched expression of miR-146a target gene sets and positively enriched expression of gene sets suppressed by the enhancer of zeste homolog 2 (EZH2) after YY1 depletion in PCa cells...
February 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28101534/pathogenicity-determinants-of-the-human-malaria-parasite-plasmodium-falciparum-have-ancient-origins
#15
Andrew J Brazier, Marion Avril, Maria Bernabeu, Maxwell Benjamin, Joseph D Smith
Plasmodium falciparum, the most deadly of the human malaria parasites, is a member of the Laverania subgenus that also infects African Great Apes. The virulence of P. falciparum is related to cytoadhesion of infected erythrocytes in microvasculature, but the origin of dangerous parasite adhesion traits is poorly understood. To investigate the evolutionary history of the P. falciparum cytoadhesion pathogenicity determinant, we studied adhesion domains from the chimpanzee malaria parasite P. reichenowi. We demonstrate that the P...
January 2017: MSphere
https://www.readbyqxmd.com/read/28101466/characterization-of-the-effect-of-drug-drug-interaction-on-protein-binding-in-concurrent-administration-of-sulfamethoxazol-and-diclofenac-sodium-using-bovine-serum-albumin
#16
Md Kamal Hossain, Amina Khatun, Mahmudur Rahman, Md Nahid Akter, Sadia Afreen Chowdhury, Sm Mahbubul Alam
Purpose: This project was aimed to determine the effect of concurrent administration of sulfamethoxazole and diclofenac sodium. Methods: Equilibrium dialysis method was adopted to study different protein binding aspects of sulfamethoxazole and diclofenac sodium. Results: Sulfamethoxazole showed two types of association constants; high affinity constant 29.0±0.20×10(6) M(-1) with lower number of binding sites of 0.7±1 and low affinity constant 1.13±0.20×10(6) M(-1) with higher number of binding sites of 3...
December 2016: Advanced Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28101376/atpase-activity-tightly-regulates-reca-nucleofilaments-to-promote-homologous-recombination
#17
Bailin Zhao, Dapeng Zhang, Chengmin Li, Zheng Yuan, Fangzhi Yu, Shangwei Zhong, Guibin Jiang, Yun-Gui Yang, X Chris Le, Michael Weinfeld, Ping Zhu, Hailin Wang
Homologous recombination (HR), catalyzed in an evolutionarily conserved manner by active RecA/Rad51 nucleofilaments, maintains genomic integrity and promotes biological evolution and diversity. The structures of RecA/Rad51 nucleofilaments provide information critical for the entire HR process. By exploiting a unique capillary electrophoresis-laser-induced fluorescence polarization assay, we have discovered an active form of RecA nucleofilament, stimulated by ATP hydrolysis, that contains mainly unbound nucleotide sites...
2017: Cell Discovery
https://www.readbyqxmd.com/read/28101368/polymorphisms-in-the-canine-monoamine-oxidase-a-maoa-gene-identification-and-variation-among-five-broad-dog-breed-groups
#18
James Sacco, Andrew Ruplin, Paul Skonieczny, Michael Ohman
BACKGROUND: In humans, reduced activity of the enzyme monoamine oxidase type A (MAOA) due to genetic polymorphisms within the MAOA gene leads to increased brain neurotransmitter levels associated with aggression. In order to study MAOA genetic diversity in dogs, we designed a preliminary study whose objectives were to identify novel alleles in functionally important regions of the canine MAOA gene, and to investigate whether the frequencies of these polymorphisms varied between five broad breed groups (ancient, herding, mastiff, modern European, and mountain)...
2017: Canine Genetics and Epidemiology
https://www.readbyqxmd.com/read/28101207/structure-function-analysis-of-dna-helicase-helq-a-new-diagnostic-marker-in-ovarian-cancer
#19
Ya-Ping Li, Jun-Juan Yang, Hui Xu, En-Yu Guo, Yan Yu
It has been previously reported that a deficiency of the helicase, POLQ-like (HELQ) gene increases the risk of ovarian cancer. The present study aimed to explore the structure-function association of HELQ and discuss the effect of molecular structure on the occurrence of tumors. ExPASy tools were employed to analyze the physicochemical properties and secondary structure of the genes. PHYRE2 Protein Fold Recognition Server was used to construct the three-dimensional model and find the ligand-binding sites of HELQ...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28101031/alectinib-induced-erythema-multiforme-and-successful-rechallenge-with-alectinib-in-a-patient-with-anaplastic-lymphoma-kinase-rearranged-lung-cancer
#20
Tatsuo Kimura, Junko Sowa-Osako, Toshiyuki Nakai, Ayako Ohyama, Tomoya Kawaguchi, Daisuke Tsuruta, Masahiko Ohsawa, Kazuto Hirata
BACKGROUND: Alectinib is an oral drug developed for the treatment of patients with fusion gene encoding echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-rearranged non-small cell lung cancer (NSCLC). Here, we present the case of a patient treated with alectinib who developed a hypersensitivity reaction with successful rechallenge treatment. CASE PRESENTATION: A 39-year-old woman who was a passive smoker was referred to Osaka City University Hospital for the evaluation of a skin event caused by treatment for NSCLC with the fusion gene EML4-ALK...
September 2016: Case Reports in Oncology
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