title: Structure-based combinatorial library design: discovery of non-peptidic inhibitors of caspases 3 and 8.
abstract: Structure-based design of a combinatorial array was carried out in order to identify non-peptidic thiomethylketone inhibitors of caspases 3 and 8. Five compounds from the designed array were active against caspase 3, and two were active against caspase 8. A 2.5-A resolution co-crystal structure of caspase 3 and a thiomethylketone array member is reported. The structure-based design strategy has proved useful for identifying caspase inhibitors.
authors.affiliation: Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. Martha_S_Head@sbphrd.com
authors.forename: M S
authors.initials: MS
authors.lastname: Head
authors.forename: M D
authors.initials: MD
authors.lastname: Ryan
authors.forename: D
authors.initials: D
authors.lastname: Lee
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.forename: C A
authors.initials: CA
authors.lastname: Janson
authors.forename: N O
authors.initials: NO
authors.lastname: Concha
authors.forename: P M
authors.initials: PM
authors.lastname: Keller
authors.forename: W E
authors.initials: WE
authors.lastname: deWolf
mesh_terms: D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D020134:Catalytic Domain; D020650:Combinatorial Chemistry Techniques; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases