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Noha S.M.,University of Innsbruck | Atanasov A.G.,University of Vienna | Schuster D.,University of Innsbruck | Schuster D.,Inte Ligand Softwareentwicklung und Consulting GmbH | And 10 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Various inflammatory stimuli that activate the nuclear factor kappa B (NF-κB) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-κB: the I kappa B kinase β (IKK-β). Therefore, IKK-β is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-β inhibitors. This model was employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored by molecular shape to rank and further prioritized virtual hits by three-dimensional shape-based alignment. One out of ten acquired and biologically tested compounds showed inhibitory activity in the low micromolar range on IKK-β enzymatic activity in vitro and on NF-κB transactivation in intact cells. Compound 8 (2-(1-adamantyl)ethyl 4-[(2,5-dihydroxyphenyl)methylamino]benzoate) represents a novel chemical class of IKK-β inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-β ligands. © 2010 Elsevier Ltd. All rights reserved. Source

Schuster D.,University of Innsbruck | Schuster D.,Inte Ligand Softwareentwicklung und Consulting GmbH | Kern L.,University of Innsbruck | Hristozov D.P.,Molecular Networks GmbH | And 12 more authors.
Combinatorial Chemistry and High Throughput Screening | Year: 2010

Nature, especially the plant kingdom, is a rich source for novel bioactive compounds that can be used as lead compounds for drug development. In order to exploit this resource, the two neural network-based virtual screening techniques novelty detection with self-organizing maps (SOMs) and counterpropagation neural network were evaluated as tools for efficient lead structure discovery. As application scenario, significant descriptors for acetylcholinesterase (AChE) inhibitors were determined and used for model building, theoretical model validation, and virtual screening. Top-ranked virtual hits from both approaches were docked into the AChE binding site to approve the initial hits. Finally, in vitro testing of selected compounds led to the identification of forsythoside A and (+)-sesamolin as novel AChE inhibitors. © 2010 Bentham Science Publishers Ltd. Source

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