Alicia Merlino
Theoretical and Computational Chemistry Group
Uruguay
Title: Nitrones as potential therapeutic agents against Alzheimer’s Disease
Biography
Biography: Alicia Merlino
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide for which there is currently no cure. One of the main reasons that has prevented the development of an effective treatment for AD is that molecular factors that cause the disease have remained elusive. Recently caspase-3 has been proposed as a potential therapeutic target for treating AD. Caspases inhibition is not an easy task because they are involved in a variety of cellular processes. However, since caspase-3 is overexpressed in brains from AD patients its selective modulation by non-covalent and selective inhibitors becomes an interesting strategy in the search of potential drugs against this neuropathology. With this in mind, our research group has been working in the capacity of a series of nitrones to inhibit caspase-3 mediated apoptosis in mouse hippocampal (HT22) cells. Moreover, the mechanism of inhibition of caspase-3 by nitrones was evaluated by means of molecular docking and molecular dynamics (MD) simulations. Most of the evaluated nitrones are able to inhibit apoptosis in neuronal HT22 cells. According to docking and MD results these molecules would be able to act as caspase-3 inhibitors by binding into a region close to the substrate binding site and causing important allosteric changes at the catalytic site. Interestingly, nitrones interact with residues that are not conserved in other caspases and therefore they could be promising selective inhibitors of caspase-3. Enzymatic assays in order to test the capacity of these nitrones to selectively inhibit caspase-3 are currently underway.