title: Methods for compound selection focused on hits and application in drug discovery.
abstract: In the context of virtual screening calculations, a multiple fingerprint-based metric is applied to generate focused compound libraries by database searching. Different fingerprints are used to facilitate a similarity step for database mining, followed by a diversity step to assemble the final library. The method is applied, for example, to build libraries of limited size for hit-to-lead development efforts. In studies designed to inhibit a therapeutically relevant protein-protein interaction, small molecular hits were initially obtained by combined fingerprint- and structure-based virtual screening and used for the design of focused libraries. We review the applied virtual screening approach and report the statistics and results of screening as well as focused library design. While the structures of lead compounds cannot be disclosed, the analysis is thought to provide an example of the interplay of different methods applied in practical lead identification.
authors.affiliation: Computer-Aided Drug Discovery, Albany Molecular Bothell Research Center Inc., Washington 98011, USA.
authors.forename: Florence L
authors.initials: FL
authors.lastname: Stahura
authors.forename: Ling
authors.initials: L
authors.lastname: Xue
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Godden
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D001665:Binding Sites; D016208:Databases, Factual; D015195:Drug Design; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D019151:Peptide Library; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: D008565:Membrane Proteins; D019151:Peptide Library; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein