Time filter

Source Type

Halle (Saale), Germany

Bobach C.,Leibniz Institute of Plant Biochemistry | Bobach C.,Ontochem GmbH | Tennstedt S.,Leibniz Institute of Plant Biochemistry | Tennstedt S.,University of Lubeck | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2014

The androgen receptor is an important pharmaceutical target for a variety of diseases. This paper presents an in silico/in vitro screening procedure to identify new androgen receptor ligands. The two-step virtual screening procedure uses a three-dimensional pharmacophore model and a docking/scoring routine. About 39,000 filtered compounds were docked with PLANTS and scored by Chemplp. Subsequent to virtual screening, 94 compounds, including 28 steroidal and 66 nonsteroidal compounds, were tested by an androgen receptor fluorescence polarization ligand displacement assay. As a result, 30 compounds were identified that show a relative binding affinity of more than 50% in comparison to 100 nM dihydrotestosterone and were classified as androgen receptor binders. For 11 androgen receptor binders of interest IC50 and Ki values were determined. The compound with the highest affinity exhibits a Ki value of 10.8 nM. Subsequent testing of the 11 compounds in a PC-3 and LNCaP multi readout proliferation assay provides insights into the potential mode of action. Further steroid receptor ligand displacement assays and docking studies on estrogen receptors α and β, glucocorticoid receptor, and progesterone receptor gave information about the specificity of the 11 most active compounds. © 2014 Elsevier Masson SAS.

Bobach C.,Leibniz Institute of Plant Biochemistry | Bobach C.,Ontochem GmbH | Schurwanz J.,Leibniz Institute of Plant Biochemistry | Franke K.,Leibniz Institute of Plant Biochemistry | And 7 more authors.
Journal of Ethnopharmacology | Year: 2014

Ethnopharmacological relevance Prostate cancer is one of the most diagnosed forms of cancer among men in western regions. Many traditional applications or phytotherapeutic concepts propose to inhibit the proliferation of prostate cancer cells. In order to detect influences of plant or fungal extracts and derived fractions on androgen receptor signaling pathways, a differentiating cell proliferation assay was established, which enables the simultaneous detection of hormonal and cytotoxic effects. Material and methods The well characterized prostate cancer cell lines LNCaP and PC-3 were used in a multiple readout assay. In all, 186 fractions of 23 traditionally used organisms were screened regarding their effects on proliferation of the two prostate cancer cell lines. The fractions were prepared by accelerated solvent extraction followed by gradient extrography. Extracts of the potential hormonally active plants Cibotium barometz, Heteropterys chrysophylla, and Sideroxylon obtusifolium (= Bumelia sartorum) were phytochemically investigated. Results Fractions from Cibotium barometz, Cortinarius rubellus, Cyrtomium falcatum, Heteropterys chrysophylla, Nephrolepis exaltata, Salvia miltiorrhiza, Sideroxylon obtusifolium, Trichilia emetica, and Trimeria grandifolia exhibited hormonal influences on prostate cancer cells. Cytotoxic activity towards human cell lines was detected for the first time for fractions from Aglaia spectabilis (A. gigantea), Nephrolepis exaltata and Cortinarius brunneus. Conclusions The differential behavior of the two prostate cancer cell lines allows the discrimination between potential androgenic or antiandrogenic activities and effects on the estrogen or glucocorticoid receptor as well as cytotoxic activities. The combined cell lines assay can help to assess the biological activities of material used in traditional medicine. © 2014 Elsevier Ireland Ltd. All rights reserved.

Mittag K.,Ontochem GmbH | Hinneburg A.,Martin Luther University of Halle Wittenberg
INFORMATIK 2010 - Service Science - Neue Perspektiven fur die Informatik, Beitrage der 40. Jahrestagung der Gesellschaft fur Informatik e.V. (GI) | Year: 2010

Information needs like searching scientific literature that involve high recall rates are difficult to satisfy with ad hoc keyword search. We propose to state queries implicitly by the specification of a set of query documents. The result of such a query is a set of answer documents that are ranked within the answer set. We describe efficient techniques to process such queries. Preliminary experiments using data from the TREC Genomics track 2005 are reported.

Ontochem Gmbh | Date: 2013-09-17

The present invention refers to neuropeptide Y receptor 1 (NPY-1) binding ligands linked to cytotoxic molecules and their use for the treatment of cancer and other diseases.

Ahrens V.M.,University of Leipzig | Kostelnik K.B.,University of Leipzig | Rennert R.,Ontochem GmbH | Bohme D.,University of Leipzig | And 6 more authors.
Journal of Controlled Release | Year: 2015

Abstract Myxobacterial tubulysins are promising chemotherapeutics inhibiting microtubule polymerization, however, high unspecific toxicity so far prevents their application in therapy. For selective cancer cell targeting, here the coupling of a synthetic cytolysin to the hY1-receptor preferring peptide [F7,P34]-neuropeptide Y (NPY) using a labile disulfide linker is described. Since hY1-receptors are overexpressed in breast tumors and internalize rapidly, this system has high potential as peptide-drug shuttle system. Molecular characterization of the cytolysin-[F7,P34]-NPY bioconjugate revealed potent receptor activation and receptor-selective internalization, while viability studies verified toxicity. Triple SILAC studies comparing free cytolysin with the bioconjugate demonstrated an intracellular mechanism of action regardless of the delivery pathway. Treatments resulted in a regulation of proteins implemented in cell cycle arrest confirming the tubulysin-like effect of the cytolysin. Thus, the cytolysin-peptide bioconjugate fused by a cleavable linker enables a receptor-specific delivery as well as a potent intracellular drug-release with high cytotoxic activity. © 2015 Published by Elsevier B.V.

Discover hidden collaborations