Introduction: Alzheimer's disease (AD), which is characterized by progressive intellectual deterioration, is the most common cause of dementia. β-Secretase (or BACE1) expression is a trigger for amyloid β peptide formation, a cause of AD, and thus is a molecular target for the development of drugs against AD. Many BACE1 inhibitors have been identified by academic and pharmaceutical research groups and a number of advanced technologies in drug discovery have been applied to the drug discovery.
Areas covered: The purpose of this review is to present and discuss the methodologies used for BACE1 inhibitor drug discovery via substrate- and structure-based design, high-throughput screening and fragment-based drug design. The authors also review the advantages and disadvantages of these methodologies.
Expert opinion: Many BACE1 inhibitors have been designed using X-ray crystal structure-based drug design as well as through in silico screening. Nevertheless, there are serious problems with regards to deciding the best X-ray crystal structure for designing BACE1 inhibitors through computational approaches. There are two prominent configurations of BACE1 but there is still room for improvement. Future developments may make it possible to identify BACE1 inhibitors as potential drug candidates.