title: Coupling structure-based design with combinatorial chemistry: application of active site derived pharmacophores with informative library design.
abstract: Protein structural information is combined with combinatorial library design in the following protocol. Active site maps are generated from protein structures. All possible 2-, 3- and 4-point pharmacophores are enumerated from the active site map and encoded as bit strings. The pharmacophores define a design space that can be used to select compounds using an informative library design tool. The method was evaluated against a collection of compounds assayed previously against a cyclin-dependent kinase target, CDK-2, starting with 23 X-ray co-crystal structures. Performance was assessed based on the number of active scaffolds selected after four rounds of iterative informative library design. The method selects compounds from 12 out of the 15 active scaffolds from the CDK-2 library and outperforms a two-dimensional similarity search and docking calculations.
authors.affiliation: DuPont Pharmaceuticals Research Laboratories, San Francisco, CA 94111, USA. jeksterowicz@combichem.com
authors.forename: John E
authors.initials: JE
authors.lastname: Eksterowicz
authors.forename: Erik
authors.initials: E
authors.lastname: Evensen
authors.forename: Christian
authors.initials: C
authors.lastname: Lemmen
authors.forename: G Patrick
authors.initials: GP
authors.lastname: Brady
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Lanctot
authors.forename: Erin K
authors.initials: EK
authors.lastname: Bradley
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Robinson
authors.forename: Peter D J
authors.initials: PD
authors.lastname: Grootenhuis
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Blaney
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000378:metabolism; D016208:Databases, Factual; D015195:Drug Design; D007990:Libraries; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases