In silico identification and crystal structure validation of caspase-3 inhibitors without a P1 aspartic acid moiety

Acta Cryst. (2011). F67, 842–850 (doi.org/10.1107/S1744309111018604)

High-resolution crystal structures in combination with fragment-based docking procedures are powerful tools for the identification of novel inhibitors. By using the fragment-based docking suite DAIM–SEED–FFLD several novel caspase-3 directed inhibitors were identified. Interestingly many of those inhibitors are lacking an aspartic acid. Although aspartic acid diminishes cell penetration, it is almost ubiquitously present in caspase inhibitors because caspases possess a stringent requirement for this amino acid. The complex structures reveal that several inhibitors utilize interactions in the prime part of the substrate-binding site.