title: Evaluation of a novel shape-based computational filter for lead evolution: application to thrombin inhibitors.
abstract: A novel shape-feature-based computational method is described and used to rapidly filter compound libraries. The computational model, built using three-dimensional conformations of active and inactive molecules, consists of a collection of whole molecule shapes and chemical feature positions that are ranked according to their correlation with activity. A small ensemble of these shapes and features is used to filter virtual compound libraries. The method is applied to two thrombin data sets and is shown to be efficient in identifying novel scaffolds with enhanced hit rates.
authors.affiliation: Deltagen Research Laboratories, 4570 Executive Drive, Suite 400, San Diego, CA 92121, USA. jsrinivasan@deltagen.com
authors.forename: Jayashree
authors.initials: J
authors.lastname: Srinivasan
authors.forename: Angelo
authors.initials: A
authors.lastname: Castellino
authors.forename: Erin K
authors.initials: EK
authors.lastname: Bradley
authors.forename: John E
authors.initials: JE
authors.lastname: Eksterowicz
authors.forename: Peter D J
authors.initials: PD
authors.lastname: Grootenhuis
authors.forename: Santosh
authors.initials: S
authors.lastname: Putta
authors.forename: Robert V
authors.initials: RV
authors.lastname: Stanton
mesh_terms: D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D008024:Ligands; D015842:Serine Proteinase Inhibitors; D013917:Thrombin