title: De novo design by pharmacophore-based searches in fragment spaces.
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.
authors.affiliation: Center for Bioinformatics, University of Hamburg, Bundesstr. 43, 20146 Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Lippert
authors.forename: Tanja
authors.initials: T
authors.lastname: Schulz-Gasch
authors.forename: Olivier
authors.initials: O
authors.lastname: Roche
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.forename: Matthias
authors.initials: M
authors.lastname: Rarey
mesh_terms: D000465:Algorithms; D020134:Catalytic Domain; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry*; D015195:Drug Design; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012984:Software
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D008024:Ligands; D010446:Peptide Fragments; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl