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Ligands and binding

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https://www.readbyqxmd.com/read/29166663/a-general-model-for-predicting-the-binding-affinity-of-reversibly-and-irreversibly-dimerized-ligands
#1
Kenneth W Foreman
Empirical data has shown that bivalent inhibitors can bind a given target protein significantly better than their monomeric counterparts. However, predicting the corresponding theoretical fold improvements has been challenging. The current work builds off the reacted-site probability approach to provide a straightforward baseline reference model for predicting fold-improvements in effective affinity of dimerized ligands over their monomeric counterparts. For the more familiar irreversibly linked bivalents, the model predicts a weak dependence on tether length and a scaling of the effective affinity with the 3/2 power of the monomer's affinity...
2017: PloS One
https://www.readbyqxmd.com/read/29166564/optical-control-of-dopamine-receptors-using-a-photoswitchable-tethered-inverse-agonist
#2
Prashant Donthamsetti, Nils Winter, Matthias Schönberger, Joshua Levitz, Cherise Stanley, Jonathan A Javitch, Ehud Y Isacoff, Dirk Trauner
Family A G protein-coupled receptors (GPCRs) control diverse biological processes and are of great clinical relevance. Their archetype rhodopsin becomes naturally light sensitive by binding covalently to the photoswitchable tethered ligand (PTL) retinal. Other GPCRs, however, neither bind covalently to ligands nor are light sensitive. We sought to impart the logic of rhodopsin to light-insensitive Family A GPCRs in order to enable their remote control in a receptor-specific, cell-type-specific and spatio-temporally precise manner...
November 22, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29166018/discovery-of-small-molecule-inhibitors-of-ubiquitin-specific-protease-7-usp7-using-integrated-nmr-and-in-silico-techniques
#3
Paola Di Lello, Richard Pastor, Jeremy M Murray, Robert A Blake, Frederick Cohen, Terry D Crawford, Joy Drobnick, Jason Drummond, Lorna Kategaya, Tracy Kleinheinz, Till Maurer, Lionel Rouge, Xianrui Zhao, Ingrid Wertz, Chudi Ndubaku, Vickie Tsui
USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53 and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical and computational approaches that led to the identification of 4-(2-aminopyridin-3-yl)-phenol compounds described by Kategaya et al.1 as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemical high-throughput screening (HTS) hits led to the discovery of a series of ligands that bind in the "palm" region of the catalytic domain of USP7 and inhibit its catalytic activity...
November 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29166011/a-cooperative-folding-unit-as-the-structural-link-for-energetic-coupling-within-a-protein
#4
Nathan W Gardner, Sarah M McGinness, Jainik Panchal, Elizabeth M Topp, Chiwook Park
Previously, we demonstrated that ligand binding to Escherichia coli cofactor-dependent phosphoglycerate mutase (dPGM), a homodimeric protein, is energetically coupled with dimerization. The equilibrium unfolding of dPGM occurs with a stable, monomeric intermediate. Binding of several non-substrate metabolites stabilizes the dimeric native form over the monomeric intermediate, reducing the population of the intermediate. Both the active site and the dimer interface appear to be unfolded in the intermediate. We hypothesized that a loop containing residues 118-152 was responsible for the energetic coupling between the dimer interface and the distal active site and was unfolded in the intermediate...
November 22, 2017: Biochemistry
https://www.readbyqxmd.com/read/29166005/self-assembly-of-tetrameric-and-hexameric-terpyridine-based-macrocycles-using-cd-ii-zn-ii-and-fe-ii
#5
Lei Wang, Zhe Zhang, Xin Jiang, Jennifer A Irvin, Changlin Liu, Ming Wang, Xiaopeng Li
The self-assembly behavior of a tritopic 2,2':6',2″-terpyridine (tpy) ligand with Cd(II), Zn(II), and Fe(II) has been exploited herein to generate a series of tetrameric and hexameric macrocycles. The main advantage of using such transition metals with an octahedral coordination geometry is their distinct coordination abilities (e.g., binding strength and reversibility). With the same ligand, this study reveals that the supramolecular structural variation between tetrameric and hexameric macrocycle architectures can be precisely controlled using different metal ions with the same coordination geometry...
November 22, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/29165903/deprotonated-indigo-as-bridging-ligand-in-cis-and-trans-configuration
#6
Goutam Kumar Lahiri
The doubly deprotonated form L2 of indigo = H2L can bind two [Ru(acac)2] complex fragments in the cis (1) and trans configuration (2), as evident from crystal structure analysis. While the latter type of N,O; N/,O/ coordination has been observed earlier, e.g. with [Ru(bpy)2]2+, leading to two equivalent six-membered ring chelates, the cis arrangement in 1 is observed here for the first time in a dinuclear complex, producing one five-membered ring chelate with N,N/ coordination and one seven-membered chelate with O,O/ coordination...
November 22, 2017: Chemistry, An Asian Journal
https://www.readbyqxmd.com/read/29165618/human-specific-mutations-and-positively-selected-sites-in-marco-confer-functional-changes
#7
Kyle E Novakowski, Nicholas V L Yap, Charles Yin, Kaori Sakamoto, Bryan Heit, G Brian Golding, Dawn M E Bowdish
Macrophage Receptor with COllagenous structure (MARCO) is a class A scavenger receptor that binds, phagocytoses, and modifies inflammatory responses to bacterial pathogens. Multiple candidate gene approach studies have shown that polymorphisms in MARCO are associated with susceptibility or resistance to Mycobacterium tuberculosis infection, but how these variants alter function is not known. To complement candidate gene approach studies, we previously used phylogenetic analyses to identify a residue, glutamine 452 (Q452), within the ligand-binding Scavenger Receptor Cysteine Rich (SRCR) domain as undergoing positive selection in humans...
November 20, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/29165489/perylenediimide-based-glycoclusters-as-high-affinity-ligands-of-bacterial-lectins-synthesis-binding-studies-and-anti-adhesive-properties
#8
Marion Donnier-Maréchal, Nicolas Galanos, Teddy Grandjean, Yoann Pascal, Ding-Kun Ji, Lei Dong, Emilie Gillon, Xiao-Peng He, Anne Imberty, Eric Kipnis, Rodrigue Dessein, Sébastien Vidal
The synthesis of eight perylenediimide-based glycoclusters was readily performed from hexa- and tetra-propargylated cores through azide-alkyne "click" conjugation. Variations in the carbohydrate epitope (Glc, Gal, Man, Fuc) and the linker arm provided molecular diversity. Interactions with LecA and LecB, two proteins involved in the adhesion of Pseudomonas aeruginosa to host tissues, were evaluated by microcalorimetry (ITC). In both cases high affinities were obtained with Kd values in the nanomolar range. Further evaluation of their anti-adhesive properties using cultured epithelial cells demonstrated their potent anti-adhesive activities against Pseudomonas aeruginosa with only 30-40% residual adhesion observed...
November 22, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29165360/dynamic-docking-a-paradigm-shift-in-computational-drug-discovery
#9
REVIEW
Dario Gioia, Martina Bertazzo, Maurizio Recanatini, Matteo Masetti, Andrea Cavalli
Molecular docking is the methodology of choice for studying in silico protein-ligand binding and for prioritizing compounds to discover new lead candidates. Traditional docking simulations suffer from major limitations, mostly related to the static or semi-flexible treatment of ligands and targets. They also neglect solvation and entropic effects, which strongly limits their predictive power. During the last decade, methods based on full atomistic molecular dynamics (MD) have emerged as a valid alternative for simulating macromolecular complexes...
November 22, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29165176/the-different-roles-of-innate-immune-receptors-in-inflammation-and-carcinogenesis-between-races
#10
Natsu Yamaguchi, Yoshimi Suzuki, M H Mahbub, Hidekazu Takahashi, Ryosuke Hase, Yasutaka Ishimaru, Hiroshi Sunagawa, Rie Watanabe, Yoshinobu Eishi, Tsuyoshi Tanabe
Innate immune factors exert widespread effects on cytokine secretion, cell survival, autophagy, and apoptosis. Nucleotide-binding and oligomerization domain-like receptors (NLRs) are members of the innate immune system in the cytosol that sense pathogens, endogenous danger molecules such as uric acid, and pollutants. Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD1 and NOD2) are components of NLR family, and ligands of these factors are γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl dipeptide (MDP), respectively...
October 11, 2017: Environmental Health and Preventive Medicine
https://www.readbyqxmd.com/read/29165067/optimized-virtual-screening-workflow-towards-target-based-polynomial-scoring-functions-for-hiv-1-protease
#11
Val Oliveira Pintro, Walter F Azevedo
BACKGROUND: One key step in the development of inhibitors for an enzyme is the application of computational methodologies to predict protein-ligand interactions. The abundance of structural and ligand-binding information for HIV-1 protease opens up the possibility to apply computational methods to develop scoring functions targeted to this enzyme. OBJECTIVE: Our goal here is to develop an integrated molecular docking approach to investigate protein-ligand interactions with focus on the HIV-1 protease...
November 20, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/29164729/identification-and-characterization-of-a-histamine-binding-lipocalin-like-molecule-from-the-relapsing-fever-tick-ornithodoros-turicata
#12
G Neelakanta, H Sultana, D E Sonenshine, J F Andersen
Lipocalins are low molecular weight membrane transporters that are abundantly expressed in the salivary glands and other tissues of ticks. In this study, we identified a lipocalin-like molecule, designated as otlip, from the soft ticks Ornithodoros turicata, the vector for the relapsing fever causing spirochete Borrelia turicatae. We noted that the expression of otlip was developmentally regulated, with adult ticks expressing significantly higher levels in comparison to the larvae or nymphal ticks. Expression of otlip was evident in both fed and unfed O...
November 22, 2017: Insect Molecular Biology
https://www.readbyqxmd.com/read/29164305/nuclear-transport-of-the-human-aryl-hydrocarbon-receptor-and-subsequent-gene-induction-relies-on-its-residue-histidine-291
#13
A Tkachenko, M Bermudez, S Irmer-Stooff, D Genkinger, F Henkler-Stephani, G Wolber, A Luch
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor involved in the metabolism of physiological substances and xenobiotics, representing an interesting target in both toxicology and pharmacology. In this study, we investigated the ligand-dependent conjunction of nuclear import of the human AHR in living cells and target gene induction. Our findings strengthen the theory that the AHR triggers a precisely defined and rapid reaction upon binding to endogenous ligands, while the xenobiotic β-naphthoflavone only induces rather unspecific and slow effects...
November 21, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29164104/targeting-dengue-virus-ns-3-helicase-by-ligand-based-pharmacophore-modeling-and-structure-based-virtual-screening
#14
Sobia A Halim, Shanza Khan, Ajmal Khan, Abdul Wadood, Fazal Mabood, Javid Hussain, Ahmed Al-Harrasi
Dengue fever is an emerging public health concern, with several million viral infections occur annually, for which no effective therapy currently exist. Non-structural protein 3 (NS-3) Helicase encoded by the dengue virus (DENV) is considered as a potential drug target to design new and effective drugs against dengue. Helicase is involved in unwinding of dengue RNA. This study was conducted to design new NS-3 Helicase inhibitor by in silico ligand- and structure based approaches. Initially ligand-based pharmacophore model was generated that was used to screen a set of 1201474 compounds collected from ZINC Database...
2017: Frontiers in Chemistry
https://www.readbyqxmd.com/read/29163897/preferential-targeting-of-i-motifs-and-g-quadruplexes-by-small-molecules
#15
Manish Debnath, Shirsendu Ghosh, Ajay Chauhan, Rakesh Paul, Kankan Bhattacharyya, Jyotirmayee Dash
i-Motifs and G-quadruplexes are dynamic nucleic acid secondary structures, which are believed to play key roles in gene expression. We herein report two peptidomimetic ligands (PBP1 and PBP2) that selectively target i-motifs and G-quadruplexes over double-stranded DNA. These peptidomimetics, regioisomeric with respect to the position of triazole/prolinamide motifs, have been synthesized using a modular method involving Cu(i)-catalyzed azide and alkyne cycloaddition. The para-isomer, PBP1 exhibits high selectivity for i-motifs while the meta-isomer PBP2 binds selectively to G-quadruplex structures...
November 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/29163891/identification-of-new-quorum-sensing-autoinducer-binding-partners-in-pseudomonas-aeruginosa-using-photoaffinity-probes
#16
Y R Baker, J T Hodgkinson, B I Florea, E Alza, W R J D Galloway, L Grimm, S M Geddis, H S Overkleeft, M Welch, D R Spring
Many bacterial species, including the human pathogen Pseudomonas aeruginosa, employ a mechanism of intercellular communication known as quorum sensing (QS), which is mediated by signalling molecules termed autoinducers. The Pseudomonas Quinolone Signal (PQS) and 2-Heptyl-3H-4-Quinolone (HHQ) are autoinducers in P. aeruginosa, and they are considered important factors in the progress of infections by this clinically relevant organism. Herein, we report the development of HHQ and PQS photoaffinity-based probes for chemical proteomic studies...
November 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/29163684/novel-peptide-screened-from-a-phage-display-library-antagonizes-the-activity-of-cc-chemokine-receptor-9
#17
Yi Hu, Aiping Ma, Shan Lin, Yang Yang, Guolin Hong
CC chemokine receptor 9 (CCR9) serves a role in the drug resistance and metastasis of tumors. In the present study, a peptide specifically bound to CCR9 was obtained and the effect on tumor cells was observed. A Ph.D.-12 phage display peptide library was used to screen for peptides binding specifically to the second extracellular loop of CCR9. The ratios of the input and output of phage clones increased gradually following three rounds of biopanning. A total of 8 positive phage clones were identified from DNA analysis...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29163468/the-role-of-natural-antibodies-to-cc-chemokine-receptor-5-in-hiv-infection
#18
REVIEW
Assunta Venuti, Claudia Pastori, Lucia Lopalco
The CC chemokine receptor 5 (CCR5) is responsible for immune and inflammatory responses by mediation of chemotactic activity in leukocytes, although it is expressed on different cell types. It has been shown to act as co-receptor for the human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV). Natural reactive antibodies (Abs) recognizing first loop (ECL1) of CCR5 have been detected in several pools of immunoglobulins from healthy donors and from several cohorts of either HIV-exposed but uninfected subjects (ESN) or HIV-infected individuals who control disease progression (LTNP) as well...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29163465/b-cell-activating-factor-and-the-b-cell-compartment-in-hiv-siv-infection
#19
REVIEW
Gwenoline Borhis, Maria Trovato, Nada Chaoul, Hany M Ibrahim, Yolande Richard
With the goal to design effective HIV vaccines, intensive studies focused on broadly neutralizing antibodies, which arise in a fraction of HIV-infected people. Apart from identifying new vulnerability sites in the viral envelope proteins, these studies have shown that a fraction of these antibodies are produced by self/poly-reactive B-cells. These findings prompted us to revisit the B-cell differentiation and selection process during HIV/SIV infection and to consider B-cells as active players possibly shaping the helper T-cell program within germinal centers (GCs)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29163463/selective-glucocorticoid-receptor-properties-of-gsk866-analogs-with-cysteine-reactive-warheads
#20
Chandra S Chirumamilla, Ajay Palagani, Balu Kamaraj, Ken Declerck, Marinus W C Verbeek, Ryabtsova Oksana, Karolien De Bosscher, Nadia Bougarne, Bart Ruttens, Kris Gevaert, René Houtman, Winnok H De Vos, Jurgen Joossens, Pieter Van Der Veken, Koen Augustyns, Xaveer Van Ostade, Annemie Bogaerts, Hans De Winter, Wim Vanden Berghe
Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective GC ligand-binding strategies, classified as selective glucocorticoid receptor (GR) agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). In the current study, GSK866 analogs with electrophilic covalent-binding warheads were developed with potential SEGRA properties to improve their clinical safety profile for long-lasting topical skin disease applications...
2017: Frontiers in Immunology
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