Scaffold morphing and in-silico studies of potential BACE1 (β-secretase) inhibitors: A hope for newer dawn in anti-Alzheimer therapeutics

Abstract Alzheimer’s disease (AD) is the prime cause for 65–80% of the dementia cases occurs due to the plaques and tangles deposition in the brain neurons leading to brain cell degeneration. β-secretase enzyme (BACE-1) is a key enzyme responsible for the deposition of extracellular plaques made of β-amyloid protein. Therefore, efforts are being applied to develop novel BACE-1 enzyme inhibitors to halt the plaque build-up. In our study, we analyzed some Elenbecestat analogues (a β-secretase inhibitor currently in clinical trials), designed by using structure-based drug designing and scaffold morphing approach at achieve superior therapeutic profile, followed by in silico studies like molecular docking, pharmacokinetics methodologies. The designed molecules showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of β-Secretase enzyme and having drug likeliness properties. Finally, the molecular dynamic studies were performed to analyses their thermodynamic stability and dynamic behavior of ligand with the active pocket of β-secretase.