De novo design by pharmacophore-based searches in fragment spaces
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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.
KeywordsDe novo design Pharmacophores Fragment-based design
TL: I would like to thank the team I worked with on the NAOMI project for the practical and emotional support: Sascha Urbaczek, Robert Fischer and Adrian Kolodzik. TSG,TL: We would like to express our gratitude for the good cooperation with the CAMM team at Roche. The fruitful discussions which we had were the foundations for the unique features in Qsearch. 3D images were created either with the UCSF Chimera package  or the MOE software suite.