Abstract
Studies of 17 analoges of 3 (SJA6017) in an in silico calpain model are reconciled to measured IC(50) values against ovine calpain. The studies validate the potential of the "model" and criteria established for inhibition as a tool to select structures for synthesis to test as calpain inhibitors. Using this screening methodology of virtual libraries led us to synthesize several inhibitors including macrocycle 33, which in vitro sheep eye lens culture experiments showed to substantially slow opacification.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Calpain / antagonists & inhibitors*
-
Calpain / chemistry
-
Calpain / genetics
-
Catalytic Domain
-
Cataract / prevention & control*
-
Databases, Factual
-
Dipeptides / chemical synthesis
-
Dipeptides / chemistry*
-
Dipeptides / pharmacology
-
Lens, Crystalline / drug effects
-
Lens, Crystalline / pathology
-
Macrocyclic Compounds / chemical synthesis
-
Macrocyclic Compounds / chemistry*
-
Macrocyclic Compounds / pharmacology
-
Models, Molecular*
-
Molecular Sequence Data
-
Mutation
-
Protein Conformation
-
Sheep
-
Structure-Activity Relationship
-
Tissue Culture Techniques
Substances
-
Dipeptides
-
Macrocyclic Compounds
-
N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal
-
Calpain