Small molecule inhibits BACE1 activity by a dual mechanism confirmed by simulations-based study.

Alzheimer's disease (AD) is a progressive and largely incurable neurodegenerative disorder that affects millions of people worldwide. It is characterised by the accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain. It is commenced by cleavage of amyloid precursor protein (APP) by β-secretase, β-site amyloid precursor protein cleaving enzyme (BACE1; also called Asp2, memapsin 2). Therefore, BACE1 is a prime target for developing therapeutics against AD. In this study, we have identified a small molecule that potentially inhibits the activity of BACE1 by interacting with the active site residues. Also, the flap region seems to be involved in enhancing the stability of the small molecule at the active site. We have used Umibecestat (CNP-520) as a positive control. Our results show that the identified molecule has a much better orientation at the active site of BACE1 than Umibecestat and inhibits by blocking the active site and modulating flap dynamics. We have utilised virtual high-throughput screening assay, ADME profiling, and blood-brain-barrier crossing ability to narrow down potential leads. The two shortlisted molecules were then subjected to atomistic molecular dynamics simulations study. Overall, our study proposes a much better inhibitor and a rational molecule for lead development against AD.