De novo design by pharmacophore-based searches in fragment spaces |
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Authors: | Tobias Lippert Tanja Schulz-Gasch Olivier Roche Wolfgang Guba Matthias Rarey |
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Institution: | (1) Center for Bioinformatics, University of Hamburg, Bundesstr. 43, 20146 Hamburg, Germany;(2) Pharmaceutical Division, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland;; |
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Abstract: | De novo ligand design supports the search for novel molecular scaffolds in medicinal chemistry projects. This search can either
be based on structural information of the targeted active site (structure-based approach) or on similarity to known binders
(ligand-based approach). In the absence of structural information on the target, pharmacophores provide a way to find topologically
novel scaffolds. Fragment spaces have proven to be a valuable source for molecular structures in de novo design that are both
diverse and synthetically accessible. They also offer a simple way to formulate custom chemical spaces. We have implemented
a new method which stochastically constructs new molecules from fragment spaces under consideration of a three dimensional
pharmacophore. The program has been tested on several published pharmacophores and is shown to be able to reproduce scaffold
hops from the literature, which resulted in new chemical entities. |
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