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Research
Schneider, G. (2010) Virtual screening: an endless staircase? Nat. Rev. Drug Discov. 9, 273-276.
Hiss, J. A., Hartenfeller, M., Schneider, G. (2010) Concepts and applications of 'natural computing' techniques in de novo drug and peptide design. Curr. Pharm. Sci. 9, 1656-1665.
The research activities of our molecular design laboratory include algorithm and software development for drug design, as well as practical applications in hit and lead finding. Here we highlight some of our current projects.
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MEDUSA - Molecular De Novo Design by Autonomous Systems AdaptationA true
challenge for computer-assisted drug design lies in the development of a
"molecule factory", i.e. a machine or robot for fully automated
unsupervised hit and lead finding. As a joint team effort, we are in the
process of realizing
such a system based on nature-inspired optimization algorithms
guiding actual compound synthesis and testing. |
Geppert, T., Bauer, S., Hiss, J. A., Conrad, E., Reutlinger, M., Schneider, P., Weisel, M., Pfeiffer, B., Altmann, K. H., Waibler, Z. and Schneider, G. (2012) Immunosuppressive small molecule discovered by structure-based virtual screening for protein-protein interaction inhibitors. Angew. Chem. Int. Ed. 51, 258-261.
Klenner, A., Hartenfeller, M., Schneider, P. and Schneider, G. (2010) 'Fuzziness' in pharmacophore-based virtual screening and de novo design. Drug Discov. Today Technol. 7, e237-e244.
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Chemically Advanced Template Search ... and beyondThe CATS topological pharmacophore descriptor was developed in 1999 for the purpose of "scaffold-hopping". We have updated and extended its scope and domain of application ever since. CATS may used for screening compound selection, focused library profiling, and de novo drug design. |
Hartenfeller, M. and Schneider, G. (2011) Enabling future drug discovery by de novo design. WIREs Comp. Mol. Sci. 1, 742-759.
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Molecular de novo designThe group has a long-standing track record in molecular de novo
design. Since 20 years, we have consequently optimized adaptive
algorithms for computer-assisted compound generation by “simulated
molecular evolution”. Ten years ago, our ligand-based de novo design software TOPAS (TOPology Assigning System) provided the basis for a fully automated evolutionary molecular design tool. Its youngest descendant, the software DOGS (Design Of Genuine Structures), employs validated chemical reactions and fragment-based building-block assembly for “scaffold-hopping”. De novo
designed compounds are analyzed using own software for “fuzzy
pharmacophore” matching, chemical landscape analysis, and automated
ligand docking. |
Geppert, T., Hoy, B., Wessler, S. and Schneider, G. (2011) Context-based identification of protein-protein interfaces and 'hot-spot' residues. Chem. Biol. 18, 344-353.
Weisel, M., Kriegl, J. M. and Schneider, G. (2010) Architectural repertoire of ligand binding pockets on protein surfaces. ChemBioChem 11, 556-563.
Reisen, F., Weisel, M., Kriegl, J. M. and Schneider, G. (2010) Self-organizing fuzzy graphs for structure-based comparison of protein pockets. J. Proteome Res. 9, 6498-6510.
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Protein-protein interface prediction and inhibitor designFor structure-based drug design we have developed the pocket extraction method PocketPicker for identification and description of ligand binding cavities, and the iPred technique for prediction of protein-protein interfaces. Using fuzzy graph theory, PoLiMorph has been conceived for mining the "pocketome" and suggest ligand-receptor binding poses without the need for explicit docking. |
Hähnke, V., Hofmann, B., Grgat, T., Proschak, E., Steinhilber, D. and Schneider, G. (2009) PhAST: Pharmacophore Alignment Search Tool. J. Comput. Chem. 30, 761-771.
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Pharmacophore Alignment Search ToolAt the interface between chem- and bioinformatics lies our virtual screening method PhAST. It transfers the methodology of global pairwise sequence alignment, which is well established for amino acid sequences, to small druglike molecules. Each molecule is transformed into an unambiguous textual representation describing its pattern of potential pharmacophoric points (PhAST string). Fragment-based atom-typing and non-linear dimensionality reduction are employed for PhAST string generation. For global pairwise sequence alignment we use an O(n2) algorithm for maximum throughput. A flexible scoring scheme allows for the accentuation of key interaction points. |
Reutlinger, M., Guba, W., Martin, R. E., Alanine, A. I., Hoffmann, T., Klenner, A., Hiss, J. A., Schneider, P. and Schneider, G. (2011) Neighborhood-preserving visualization of adaptive structure-activity landscapes and application to drug discovery. Angew. Chem. Int. Ed. 50, 11633-11636.
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Pharmacophore DictionaryWe develop new methods for projecting and visualizing high-dimensional chemical data. Such "road maps" are valuable tools for drug design and prediction of activity profiles including unwanted side-effects. Bioactive substances are grouped into activity classes based on "fuzzy" representations of their pharmacophoric features. The resulting maps can be used to visualize and analyze the structure-activity landscape. |
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