Molecular Modelling for Enzyme Inhibition: A Search for a New Treatment for Cataract and New Antimicrobials and Herbicides

There have been several reports that cataract development results from unregulated Ca2+ mediated degradation of lens crystallins. The calpain isoform m-calpain, a cysteine protease, is known to be a major player in cataract formation in rodent lenses and recent evidence indicates that over-activation by Ca2+ causes cataractogenesis in other mammals. Molecular modelling studies of seventeen analogues of compound SJA6017 (our lead compound) in a calpain model are compared to measured IC50 values against ovine calpain. The studies validated the potential of the ‘model’, method and defined activity criteria that could be used as a tool to select molecules to synthesize as potential calpain inhibitors. Using this screening methodology and two virtual libraries of potential inhibitory molecules led to the synthesis of several inhibitors including macrocyclic 811. In vitro sheep eye lens culture experiments showed that macrocycle 811 possessed the characteristics to slow cataractogenesis