Structure-based combinatorial library design: discovery of non-peptidic inhibitors of caspases 3 and 8.
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.
Head
M S
MS
Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. Martha_S_Head@sbphrd.com
Ryan
M D
MD
Lee
D
D
Feng
Y
Y
Janson
C A
CA
Concha
N O
NO
Keller
P M
PM
deWolf
W E
WE
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
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases