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Comparison of a homology model and the crystallographic structure of human 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) in a structure-based identification of inhibitors

All Rights Reserved. Comparison of a homology model and the crystallographic structure of human 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) in a structure-based identification of inhibitors. Miguet, Laurence; Zhang, Ziding; Barbier, Maryse; Grigorov, Martin G. ( BioAnalytical Science, Nestle Research Center, Nestec Ltd, Lausanne CH-1000, Switz.). Journal of Computer-Aided Molecular Design, 20(2), 67-81 (English) 2006 Springer. CODEN: JCADEQ. ISSN: 0920-654X. DOCUMENT TYPE: Journal CA Section: 7 (Enzymes) Human 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) catalyzes the interconversion of cortisone into active cortisol. 11bHSD1 inhibition is a tempting target for the treatment of a host of human disorders that might benefit from blockade of glucocorticoid action, such as obesity, metabolic syndrome, and diabetes type 2. Here, we report an in silico screening study aimed at identifying new selective inhibitors of human 11bHSD1 enzyme. In the first step, homol. modeling was employed to build the 3D structure of 11bHSD1. Further, mol. docking was used to validate the predicted model by showing that it was able to discriminate between known 11bHSD1 inhibitors or substrates and non-inhibitors. The homol. model was found to reproduce closely the crystal structure that became publicly available in the final stages of this work. Finally, we carried out structure-based virtual screening expts. on both the homol. model and the crystallog. structure with a database of 114'000 natural mols. Among these, 15 mols. were consistently selected as inhibitors based on both the model and crystal structures of the enzyme, implying a good quality for the homol. model. Among these putative 11bHSD1 inhibitors, two were flavonone derivs. 87893-55-8 and 1191-95-3 are just another two chemicals used in this study. that have already been shown to be potent inhibitors of the enzyme. .

Molecular basis for the direct inhibition of AP-1 DNA binding by 15-deoxy-D12,14-prostaglandin J2

Molecular basis for the direct inhibition of AP-1 DNA binding by 15-deoxy-D12,14-prostaglandin J2. Perez-Sala, Dolores; Cernuda-Morollon, Eva; Canada, F. Javier ( Departamento de Estructura y Funcion de Proteinas, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Madrid 28040, Spain). Journal of Biological Chemistry, 278(51), 51251-51260 (English) 2003 American Society for Biochemistry and Molecular Biology. CODEN: JBCHA3. ISSN: 0021-9258. DOCUMENT TYPE: Journal CA Section: 2 (Mammalian Hormones) Cyclopentenone prostaglandins may interfere with cellular functions by multiple mechanisms.Several reagents with their cas registry numbers 87893-55-8 and 52-90-4 are used here. The cyclopentenone 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2) has been reported to inhibit the activity of the transcription factor AP-1 in several exptl. settings. We have explored the possibility of a direct interaction of 15d-PGJ2 with AP-1 proteins. Here we show that 15d-PGJ2 covalently modifies c-Jun and directly inhibits the DNA binding activity of AP-1. The modification of c-Jun occurs both in vitro and in intact cells as detected by labeling with biotinylated 15d-PGJ2 and mass spectrometry anal. Attachment of the cyclopentenone prostaglandin occurs at cysteine 269, which is located in the c-Jun DNA binding domain. In addn., 15d-PGJ2 can promote the oligomerization of a fraction of c-Jun through the formation of intermol. disulfide bonds or 15d-PGJ2-bonded dimers. Our results identify a novel site of interaction of 15d-PGJ2 with the AP-1 activation pathway that may contribute to the complex effects of cyclopentenone prostaglandins on the cellular response to pro-inflammatory agents. They also show the first evidence for the induction of protein crosslinking by 15d-PGJ2. .