Search results for "Screening"
showing 10 items of 1150 documents
Pyrazolo[3,4-h]quinolines promising photosensitizing agents in the treatment of cancer.
2015
A new series of pyrazolo[3,4-h]quinolines, heteroanalogues of angelicin was conveniently prepared with a broad substitution pattern. A large number of derivatives was obtained and the cellular photocytotoxicity was evaluated in vitro against 5 different human tumor cell lines with GI50 values reaching the nanomolar level (14.52e0.04 mM). Selected compounds were able to photoinduce a massive cell death with the involvement of mitochondria. Their photodamage cellular targets were proteins and lipids and they did not cause any kind of DNA photodamage. This latter event is of considerable importance in the modulation of long term side effects, generally associated with the use of classical furo…
Identification of Plakortide E from the Caribbean Sponge Plakortis halichondroides as a Trypanocidal Protease Inhibitor using Bioactivity-Guided Frac…
2014
In this paper, we report new protease inhibitory activity of plakortide E towards cathepsins and cathepsin-like parasitic proteases. We further report on its anti-parasitic activity against Trypanosoma brucei with an IC50 value of 5 mu M and without cytotoxic effects against J774.1 macrophages at 100 mu M concentration. Plakortide E was isolated from the sponge Plakortis halichondroides using enzyme assay-guided fractionation and identified by NMR spectroscopy and mass spectrometry. Furthermore, enzyme kinetic studies confirmed plakortide E as a non-competitive, slowly-binding, reversible inhibitor of rhodesain.
Development of Novel Selective Peptidomimetics Containing a Boronic Acid Moiety, Targeting the 20S Proteasome as Anticancer Agents
2014
This paper describes the design, synthesis, and biological evaluation of peptidomimetic boronates as inhibitors of the 20S proteasome, a validated target in the treatment of multiple myeloma. The synthesized compounds showed a good inhibitory profile against the ChT-L activity of 20S proteasome. Compounds bearing a β-alanine residue at the P2 position were the most active, that is, 3-ethylphenylamino and 4-methoxyphenylamino (R)-1-{3-[4-(substituted)-2-oxopyridin-1(2H)-yl]propanamido}-3-methylbutylboronic acids (3 c and 3 d, respectively), and these derivatives showed inhibition constants (Ki ) of 17 and 20 nM, respectively. In addition, they co-inhibited post glutamyl peptide hydrolase act…
Extracellular loop 2 of G protein-coupled olfactory receptors is critical for odorant recognition
2021
International audience; G protein-coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed in non-olfactory tissues and emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of a larger mechanism for odor discrimination. Here, we demonstrate that the OR extracellular loop 2 (ECL2) plays critical roles in OR promiscuity and specificity. Using site-directed mutagenesis and molecular modeling, we constructed 3D OR models in which ECL2 forms a lid over the orthosteric pocket. We demonstrate using molecular dynamics simulations that ECL2 controls the shape and the volume of the odorant-binding pocket, m…
Getting Docking into Shape Using Negative Image-Based Rescoring
2019
The failure of default scoring functions to ensure virtual screening enrichment is a persistent problem for the molecular docking algorithms used in the structure-based drug discovery. To remedy this problem, elaborate rescoring and post-processing schemes have been developed with a varying degree of success, specificity, and cost. The negative imagebased rescoring (R-NiB) has been shown to improve the flexible docking performance markedly with a variety of drug targets.The yield improvement is achieved by comparing the alternative docking poses against the negative image of the target protein’s ligand-binding cavity. In other words, the shape and electrostatics of the binding pocket is dir…
A TR-FRET based functional assay for screening activators of CARM1
2013
Epigenome is an emerging field that demands selective cell-permeable chemical probes to perturb, especially in vivo, the activity of specific enzymes involved in modulating the epigenetic codes. Coactivator Associated Arginine (R) Methyltransferase 1 (CARM1) is a coactivator of estrogen receptor α (ERα), the main target in human breast cancer. We previously showed that overexpression of CARM1 by two-fold in MCF7 breast cancer cells increased the expression of ERα-target genes involved in differentiation and reduced cell proliferation, leading to the hypothesis that activating CARM1 by chemical activators may be therapeutically effective in breast cancer. Selective, potent, cell-permeable CA…
Protein Biomarkers of Bovine Defective Meats at a Glance: Gel-Free Hybrid Quadrupole-Orbitrap Analysis for Rapid Screening
2021
An understanding of biological mechanisms that could be involved in the stress response of animal cattle prior to slaughter is critical to create effective strategies aiming at the production of high-quality meat. The sarcoplasmic proteome of directly extracted samples from normal and high ultimate pH (pHu) meat groups was studied through a straightforward gel-free strategy supported by liquid chromatography hybrid quadrupole-Orbitrap high-resolution mass spectrometry (LC-HRMS) analysis. A stepped proteomic pipeline combining rapid biomarker hunting supported by qualitative protein Mascot scores followed by targeted label-free peptide quantification revealed 26 descriptors that characterize…
Current density maps, magnetizability, and nuclear magnetic shielding tensors of bis-heteropentalenes. II. Furo-furan Isomers
2004
Magnetic susceptibility and nuclear magnetic shielding at the nuclei of bis-heteropentalenes formed by two furan units ([2,3-b], [3,2-b], [3,4-b], and [3,4-c] isomers) have been computed by several approximated techniques and a large Gaussian basis set to achieve near Hartree–Fock estimates. Ab initio models of the ring currents induced by a magnetic field normal to the molecular plane were obtained for the three isomeric systems of higher symmetry, showing that the π electrons give rise to intense diamagnetic circulation. The π currents are responsible for enhanced magnetic anisotropy and strong out-of-plane proton deshielding. The theoretical findings are used to build up a “diatropicity …
Psychometrische Evaluation und Normwerte einer Ultrakurzform der Sense of Coherence Scale “SOC-3”
2019
ZusammenfassungKohärenzsinn ist eine psychische Ressource, die maßgeblich zu einem adaptiven Coping im Umgang mit belastenden Situationen beiträgt. In der vorliegenden Studie untersuchen wir eine Ultrakurzform der Sense of Coherence Scale (SOC-3) in einer repräsentativen Stichprobe der deutschen Bevölkerung (N=2.018). Das 3-Item-Modell wies exzellente Gütekriterien sowie eine akzeptable Reliabilität auf. Über Altersgruppen und Geschlecht konnte partielle strikte Messinvarianz des Modells nachgewiesen werden. In Bezug auf Konstruktvalidität demonstrierten unsere Analysen starke Überschneidungen der SOC-3 mit längeren SOC-Versionen (−9 und−29). Analog zu den SOC-Langversionen wurden erwartung…
Imaging the COVID-19: a practical guide
2021
The Coronavirus Disease 2019 (COVID-19) represents the first medical catastrophe of the new millennium. Although imaging is not a screening test for COVID-19, it plays a crucial role in evaluation and follow-up of COVID-19 patients. In this paper, we will review typical and atypical imaging findings of COVID-19.