• cns
• fbdd
• fragment
• inhibition
• ischemic
• keap1
• nrf2
• oxidative
• ppi
• ros
• sar
• spr
• stress
• stroke
• synthesis

Ischemic stroke is a debilitating disease that can lead to severe sequelae and it is one of the major leading cause of death worldwide. An occlusion of a blood vessel reduces the oxygen supply to the brain and affects the proper functioning of that area. Oxidative stress of cells plays a key role in the ischemic cascade: when the balance between the production of ROS (Reactive Oxygen Species) and antioxidant species is affected, a great number of radicals and reactive species are produced and this results in severe injuries.The nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in the production of antioxidant enzymes. Therefore, targeting the interaction with its repressor, the protein Kelch-like ECH-associated protein 1 (Keap1), has emerged as a therapeutic solution to oxidative stress in the central nervous system (CNS). At present, there are some known molecules able to inhibit this protein-protein interaction (PPI), but they lack permeability to the CNS due to their molecular weight and their physicochemical properties. Aim of this project is to design and develop novel small molecules Nrf2-Keap1 PPI inhibitor by exploiting fragment-based drug discovery (FBDD) and a fragment deconstruction-reconstruction approach. Known ligands have been deconstructed into 77 small fragments, that in this project are optimized by growing, linking or merging approaches. Preliminary tests of the new compounds interestingly show that some of the fragments bind in the domain. In conclusion, this approach could pave the way for the discovery of future Nrf2-Keap1 PPI inhibitors.