Tethering identifies fragment that yields potent inhibitors of human caspase-1

Disulfide Tethering((R)) was applied to the active site of human caspase-1, resulting in the discovery of a novel, tricyclic molecular fragment that selectively binds in S4. This fragment was developed into a class of potent inhibitors of human caspase-1. Several key analogues determined the optimal distance of the tricycle from the catalytic residues, the relative importance of various features of the tricycle, and the importance of the linker. (c) 2005 Elsevier Ltd. All rights reserved.