Docking studies suggest the important role of interactions among the catalytic dyad and inhibitors for designing Bace1 specific inhibitors

Abstract

Alzheimer disease (AD) is the most devastating and widespread neurodegenerative disorder around the globe. Insoluble protein aggregates originate from beta amyloid peptides is the hall mark of the disease. These peptides are produced via cleavage of Amyloid Precursor Protein (APP) by Bace1 enzyme. Therefore, finding a drug that will specifically inhibit this enzyme is one of the attractive approaches for AD treatment. Here, we assessed the affinity of 323 inhibitors that have co-crystallized with Bace1 enzyme towards two structurally related enzymes Bace2 and CatD by two different docking software Glide-QPLD and GOLD. Based on two docking results, 3% of all ligands have been found to prefer Bace1 enzyme over the other two enzymes. Interestingly, all of these ligands have –NH2 functional groups interacting with the catalytic dyad (Asp80 and Asp 276), which suggests the important role of the –NH 2 adduct in designing Bace1 specific inhibitors.