Identification of potential BACE-1 selective inhibitors against Alzheimer’s disease

Abstract Alzheimer’s disease (AD) is a neurodegenerative disease and principal cause of dementia, affecting more than 55 million people worldwide. The amyloid cascade hypothesis proposes that the β-amyloid peptides, produced by the cleavage of the Amyloid Precursor Protein by BACE-1, are responsible for the onset of the disease. Therefore, BACE-1 has been a target of research and drug design for AD treatment. BACE-1 has a homolog, BACE-2, which is not related to AD and its present and other metabolic pathways. Thus, the design of drugs to treat AD needs to be BACE-1 selective; however, this is not reality for the BACE-1 inhibitors that achieved clinical trials. This work aimed to identify the structural, steric and electronic requirements for the selective inhibition of BACE-1 guided using computational techniques, such as pharmacophore models, molecular docking, molecular dynamic simulations, and free energy calculation. A potential selective BACE-1 inhibitor and selectivity requirements were identified.