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Active Ligands (active + ligand)

Distribution by Scientific Domains
Chemistry75%

Selected Abstracts

Intracellular degradation of somatostatin-14 following somatostatin-receptor 3-mediated endocytosis in rat insulinoma cells

FEBS JOURNAL, Issue 19 2008
Dirk Roosterman
Somatostatin receptor (SSTR) endocytosis influences cellular responsiveness to agonist stimulation and somatostatin receptor scintigraphy, a common diagnostic imaging technique. Recently, we have shown that SSTR1 is differentially regulated in the endocytic and recycling pathway of pancreatic cells after agonist stimulation. Additionally, SSTR1 accumulates and releases internalized somatostatin-14 (SST-14) as an intact and biologically active ligand. We also demonstrated that SSTR2A was sequestered into early endosomes, whereas internalized SST-14 was degraded by endosomal peptidases and not routed into lysosomal degradation. Here, we examined the fate of peptide agonists in rat insulinoma cells expressing SSTR3 by biochemical methods and confocal laser scanning microscopy. We found that [125I]Tyr11-SST-14 rapidly accumulated in intracellular vesicles, where it was degraded in an ammonium chloride-sensitive manner. In contrast, [125I]Tyr1-octreotide accumulated and was released as an intact peptide. Rhodamine-B-labeled SST-14, however, was rapidly internalized into endosome-like vesicles, and fluorescence signals colocalized with the lysosomal marker protein cathepsin D. Our data show that SST-14 was cointernalized with SSTR3, was uncoupled from the receptor, and was sorted into an endocytic degradation pathway, whereas octreotide was recycled as an intact peptide. Chronic stimulation of SSTR3 also induced time-dependent downregulation of the receptor. Thus, the intracellular processing of internalized SST-14 and the regulation of SSTR3 markedly differ from the events mediated by the other SSTR subtypes. [source]

Platinum-based anticancer agents: Innovative design strategies and biological perspectives

MEDICINAL RESEARCH REVIEWS, Issue 5 2003
Yee-Ping Ho
Abstract The impact of cisplatin on cancer chemotherapy cannot be denied. Over the past 20 years, much effort has been dedicated to discover new platinum-based anticancer agents that are superior to cisplatin or its analogue, carboplatin. Most structural modifications are based on changing one or both of the ligand types coordinated to platinum. Altering the leaving group can influence tissue and intracellular distribution of the drug, whereas the carrier ligand usually determines the structure of adducts formed with DNA. DNA,Pt adducts produced by cisplatin and many of its classical analogues are almost identical, and would explain their similar patterns of tumor sensitivity and susceptibility to resistance. Recently some highly innovative design strategies have emerged, aimed at overcoming platinum resistance and/or to introduce novel mechanisms of antitumor action. Platinum compounds bearing the 1,2-diaminocyclohexane carrier ligand; and those of multinuclear Pt complexes giving rise to radically different DNA,Pt adducts, have resulted in novel anticancer agents capable of circumventing cisplatin resistance. Other strategies have focused on integrating biologically active ligands with platinum moieties intended to selectively localizing the anticancer properties. With the rapid advance in molecular biology, combined with innovation, it is possible new Pt-based anticancer agents will materialize in the near future. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 5, 633,655, 2003 [source]

,tieredScreen' , Layered Virtual Screening Tool for the Identification of Novel Estrogen Receptor Alpha Modulators

MOLECULAR INFORMATICS, Issue 5 2010
Yidong Yang
Abstract A novel tiered Structure-Based (SB) Virtual Screening (VS) workflow called tieredScreen was designed and implemented. The automated protocol utilises diverse computational tools in a synergistic manner to reduce false positives and increase the likelihood of converging on putative active molecules. The performance of the novel VS workflow was validated using the Directory of Useful Decoys (DUD) Estrogen Receptor , (ER,) antagonist dataset, and successfully deployed for the identification of novel antagonists of ER, from a screening collection of ca. 160,000 commercially available compounds. As well as yielding nanomolar (nM) active ligands identified previously through a docking only protocol, from a selection of eight virtual hits suggested by tieredScreen, four novel nM ER, binding chemotypes were identified and biologically validated , demonstrating the applicability of a tiered intervention for virtual screening. [source]

GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity

BRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2008
H A Overton
GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (,-cells) and gastrointestinal tract (enteroendocrine cells) in humans. De-orphanization of GPR119 has revealed two classes of possible endogenous ligands, viz., phospholipids and fatty acid amides. Of these, oleoylethanolamide (OEA) is one of the most active ligands tested so far. This fatty acid ethanolamide is of particular interest because of its known effects of reducing food intake and body weight gain when administered to rodents. Agonists at the GPR119 receptor cause an increase in intracellular cAMP levels via G,s coupling to adenylate cyclase. In vitro studies have indicated a role for GPR119 in the modulation of insulin release by pancreatic ,-cells and of GLP-1 secretion by gut enteroendocrine cells. The effects of GPR119 agonists in animal models of diabetes and obesity are reviewed, and the potential value of such compounds in future therapies for these conditions is discussed. British Journal of Pharmacology (2008) 153, S76,S81; doi:10.1038/sj.bjp.0707529; published online 26 November 2007 [source]