Conformationally restricted hydantoin-based peptidomimetics as inhibitors of caspase-3 with basic groups allowed at the S3 enzyme subsite.
By using a combination of molecular modeling, combinatorial chemistry, and biological essays, novel scaffold molecules for the inhibition of caspase-3 have been developed. These compounds have an overall attenuated negative charge and show similar IC(50) values for both recombinant and human endogenous caspase-3. This might provide the basis for a novel strategy for the discovery of potent and more druglike inhibitors of caspase-3.
Vázquez
Jesús
J
Institute for Research in Biomedicine, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain.
García-Jareño
Alicia
A
Mondragón
Laura
L
Rubio-Martinez
Jaime
J
Pérez-Payá
Enrique
E
Albericio
Fernando
F
D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D061945:Caspase Inhibitors; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006827:Hydantoins / Q000737:chemistry*; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D006827:Hydantoins; D010455:Peptides; D011994:Recombinant Proteins