scholarly journals Identifying new liver X receptor alpha modulators and distinguishing between agonists and antagonists by crystal ligand pocket screening

2020 ◽  
Vol 12 (13) ◽  
pp. 1227-1237
Author(s):  
Jia-Hau Lee ◽  
Chien-Fu Huang ◽  
Yi-Jing Chuang ◽  
Chang-Yin Lee ◽  
Wen-Hao Yu ◽  
...  
Keyword(s):  
Binding Sites ◽  
Binding Pocket ◽  
X Ray ◽  
Gene Assay ◽  
Pharmacological Interest ◽  
Ligand Binding Sites ◽  
Inflammatory Processes ◽  
New Compounds ◽  
Liver X Receptor Alpha

Background: Modulators of LXRα are of high pharmacological interest as LXRα regulates fatty acid metabolism, inflammatory processes and cancer. We aim to identify new LXRα modulators and to recognize a distinguishable feature of agonists. Results&methodology: The ligand self-dock and largest-cavity-size searching purposely located two appropriate ligand-binding sites to reach the two aims. One is identifying the new modulators from Maybridge library. 20 new compounds are confirmed by the in vitro reporter gene assay. The other is denoting an agonist by at least one best docking pose having one hydrogen bond to LXRα Helix12 His421. Conclusion: Based on the quality x-ray binding pocket, we can identify new LXRα modulators and distinguish between agonists and antagonists by molecular docking.

scholarly journals Analysis of the structural requirements of sugar binding to the liver, brain and insulin-responsive glucose transporters expressed in oocytes

1993 ◽  
Vol 294 (3) ◽  
pp. 753-760 ◽  
Author(s):  
C A Colville ◽  
M J Seatter ◽  
G W Gould
Keyword(s):  
Hydrogen Bond ◽  
Binding Sites ◽  
Glucose Transporters ◽  
Binding Pocket ◽  
Structural Basis ◽  
Sugar Binding ◽  
Glucose Analogues ◽  
Sugar Recognition

We have expressed the liver (GLUT 2), brain (GLUT 3) and insulin-responsive (GLUT 4) glucose transporters in oocytes from Xenopus laevis by microinjection of in vitro-transcribed mRNA. Using a range of halogeno- and deoxy-glucose analogues, and other hexoses, we have studied the structural basis of sugar binding to these different isoforms. We show that a hydrogen bond to the C-3 position is involved in sugar binding for all three isoforms, but that the direction of this hydrogen bond is different in GLUT 2 from either GLUT 1, 3 or 4. Hydrogen-bonding at the C-4 position is also involved in sugar recognition by all three isoforms, but we propose that in GLUT 3 this hydrogen bond plays a less significant role than in GLUT 2 and 4. In all transporters we propose that the C-4 position is directed out of the sugar-binding pocket. The role of the C-6 position is also discussed. In addition, we have analysed the ability of fructopyranose and fructofuranose analogues to inhibit the transport mediated by GLUT2. We show that fructofuranose analogues, but not fructopyranose analogues, are efficient inhibitors of transport mediated by GLUT 2, and therefore suggest that GLUT 2 accommodates D-glucose as a pyranose ring, but D-fructose as a furanose ring. Models for the binding sites of GLUT 2, 3 and 4 are presented.

Isolation and structures of the uprolides. I. Thirteen new cytotoxic cembranolides from the Caribbean gorgonian Euniceamammosa

1995 ◽  
Vol 73 (5) ◽  
pp. 643-654 ◽  
Author(s):  
Abimael D. Rodríguez ◽  
Ivette C. Piña ◽  
Javier J. Soto ◽  
Dalila R. Rojas ◽  
Charles L. Barnes
Keyword(s):  
Nuclear Magnetic Resonance Analysis ◽  
X Ray Diffraction ◽  
X Ray ◽  
Correlation Studies ◽  
Resonance Analysis ◽  
Eupalmerin Acetate ◽  
Chemical Correlation ◽  
The Caribbean ◽  
New Compounds

Thirteen new cembranolide diterpenoids, uprolides 3–15, have been isolated from the Caribbean gorgonian Euniceamammosa collected off the West coast of Puerto Rico. Several known metabolites, such as eupalmerin acetate (1) and eupalmerin (2), were also isolated from the same organism. The structures of the new compounds, which also showed modest in vitro cytotoxic activity, were assigned on the basis of extensive nuclear magnetic resonance analysis, chemical correlation studies, and by comparison with analogous spectral data from known cembranolide diterpenoids. One structure (3) was confirmed by X-ray diffraction analysis. Keywords: uprolides, Euniceamammosa, cytotoxicity, Caribbean, gorgonian.

scholarly journals Transcriptional Repression of the VC2105 Protein by Vibrio FadR Suggests that It Is a New Auxiliary Member of thefadRegulon

2016 ◽  
Vol 82 (9) ◽  
pp. 2819-2832 ◽  
Author(s):  
Rongsui Gao ◽  
Jingxia Lin ◽  
Han Zhang ◽  
Youjun Feng
Keyword(s):  
Transcriptional Regulation ◽  
Fatty Acid ◽  
Ligand Binding ◽  
Binding Site ◽  
Binding Sites ◽  
Regulatory Proteins ◽  
Content Type ◽  
Ligand Binding Sites

ABSTRACTRecently, our group along with others reported that theVibrioFadR regulatory protein is unusual in that, unlike the prototypicalfadRproduct ofEscherichia coli, which has only one ligand-binding site,VibrioFadR has two ligand-binding sites and represents a new mechanism for fatty acid sensing. The promoter region of thevc2105gene, encoding a putative thioesterase, was mapped, and a putative FadR-binding site (AA CTG GTA AGA GCA CTT) was proposed. Different versions of the FadR regulatory proteins were prepared and purified to homogeneity. Both electrophoretic mobility shift assay (EMSA) and surface plasmon resonance (SPR) determined the direct interaction of thevc2105gene with FadR proteins of various origins. Further, EMSAs illustrated that the addition of long-chain acyl-coenzyme A (CoA) species efficiently dissociates thevc2105promoter from the FadR regulator. The expression level of theVibrio cholerae vc2105gene was elevated 2- to 3-fold in afadRnull mutant strain, validating that FadR is a repressor for thevc2105gene. The β-galactosidase activity of avc2105-lacZtranscriptional fusion was increased over 2-fold upon supplementation of growth medium with oleic acid. Unlike thefadDgene, a member of theVibrio fadregulon, the VC2105 protein played no role in bacterial growth and virulence-associated gene expression ofctxAB(cholera toxin A/B) andtcpA(toxin coregulated pilus A). Given that the transcriptional regulation ofvc2105fits the criteria for fatty acid degradation (fad) genes, we suggested that it is a new member of theVibrio fadregulon.IMPORTANCETheVibrioFadR regulator is unusual in that it has two ligand-binding sites. Different versions of the FadR regulatory proteins were prepared and characterizedin vitroandin vivo. An auxiliaryfadgene (vc2105) fromVibriowas proposed that encodes a putative thioesterase and has a predicted FadR-binding site (AAC TGG TA A GAG CAC TT). The function of this putative binding site was proved using both EMSA and SPR. Furtherin vitroandin vivoexperiments revealed that theVibrioFadR is a repressor for thevc2105gene. UnlikefadD, a member of theVibrio fadregulon, VC2105 played no role in bacterial growth and expression of the two virulence-associated genes (ctxABandtcpA). Therefore, since transcriptional regulation ofvc2105fits the criteria forfadgenes, it seems likely thatvc2105acts as a new auxiliary member of theVibrio fadregulon.

scholarly journals Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4739
Author(s):  
Duc Hoàng Lande ◽  
Abed Nasereddin ◽  
Arne Alder ◽  
Tim W. Gilberger ◽  
Ron Dzikowski ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Pocket ◽  
Human Cell Line ◽  
Docking Studies ◽  
Antimalarial Drugs ◽  
In Vitro Screening ◽  
Rational Development ◽  
Biological Target ◽  
New Compounds

Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.

scholarly journals Anti-Food Allergic Compounds from Penicillium griseofulvum MCCC 3A00225, a Deep-Sea-Derived Fungus

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 224
Author(s):  
Cui-Ping Xing ◽  
Dan Chen ◽  
Chun-Lan Xie ◽  
Qingmei Liu ◽  
Tian-Hua Zhong ◽  
...  
Keyword(s):  
Deep Sea ◽  
Spectroscopic Data ◽  
Positive Control ◽  
X Ray ◽  
X Ray Crystallography ◽  
Ic50 Value ◽  
Penicillium Griseofulvum ◽  
New Compounds ◽  
Basophilic Leukemia

Ten new (1–10) and 26 known (11–36) compounds were isolated from Penicillium griseofulvum MCCC 3A00225, a deep sea-derived fungus. The structures of the new compounds were determined by detailed analysis of the NMR and HRESIMS spectroscopic data. The absolute configurations were established by X-ray crystallography, Marfey’s method, and the ICD method. All isolates were tested for in vitro anti-food allergic bioactivities in immunoglobulin (Ig) E-mediated rat basophilic leukemia (RBL)-2H3 cells. Compound 13 significantly decreased the degranulation release with an IC50 value of 60.3 μM, compared to that of 91.6 μM of the positive control, loratadine.

Evaluation of Commercial Tritium Standards: A Significant Source of Error in Quantitative Autoradiography

1996 ◽  
Vol 54 ◽  
pp. 460-461
Author(s):  
J. Nissanov ◽  
L. Rioux
Keyword(s):  
Binding Sites ◽  
Implicit Assumption ◽  
Absolute Concentration ◽  
X Ray ◽  
Tissue Sections ◽  
Calibration Sets ◽  
Ligand Binding Sites ◽  
Radioactive Concentration ◽  
Source Of Error

Using quantitative receptor autoradiography (QAR), it is possible to investigate the distribution of ligand binding sites as well as binding affinity. Accuracy in this technique is critically dependent on the quality of available radioactive calibration standards. For autoradiography using tritiated ligands, commercial 3H standards are available. These are also used, after cross-calibrating, as convenient standards for short-lived radioisotopes for which commercial standards are not available. A common practice in QAR is to appose these standards, each a slide containing 14 plastics of known radioactive concentration, along with the tissue sections on each sheet of x-ray film and to use these to produce a calibration curve and assign absolute concentration to densitometric measurements taken from the film. Typically, experimenters use multiple standards in their studies and directly compare data calibrated using different calibration sets. To our knowledge, only one study has tested the implicit assumption that the standards, once corrected for decay, are equivalent. That study concluded that the variability among standards is low. We revisit the issue.

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