title: A validation study on the practical use of automated de novo design.
abstract: The de novo design program Skelgen has been used to design inhibitor structures for four targets of pharmaceutical interest. The designed structures are compared to modeled binding modes of known inhibitors (i) visually and (ii) by means of a novel similarity measure considering the size and spatial proximity of the maximum common substructure of two small molecules. It is shown that the Skelgen algorithm generates representatives of many inhibitor classes within a very short time and that the new similarity measure is useful for comparing and clustering designed structures. The results demonstrate the necessity of properly defining search constraints in practical applications of de novo design.
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Stahl
authors.forename: Nikolay P
authors.initials: NP
authors.lastname: Todorov
authors.forename: Tim
authors.initials: T
authors.lastname: James
authors.forename: Harald
authors.initials: H
authors.lastname: Mauser
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Boehm
authors.forename: Philip M
authors.initials: PM
authors.lastname: Dean
mesh_terms: D000465:Algorithms; D001331:Automation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular
chemical_list: D004791:Enzyme Inhibitors